{"gene":"NOS1AP","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1998,"finding":"CAPON (NOS1AP) was identified as a novel nNOS-associated protein that interacts with the nNOS PDZ domain through its C-terminus. CAPON competes with PSD95 for interaction with nNOS, and overexpression of CAPON results in loss of PSD95/nNOS complexes in transfected cells.","method":"Co-immunoprecipitation, transfection/overexpression in cells, competition binding assay","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with functional overexpression readout, foundational paper replicated by many subsequent studies","pmids":["9459447"],"is_preprint":false},{"year":2000,"finding":"CAPON (NOS1AP) selectively interacts with Dexras1, a brain-enriched Ras-family small G protein, forming a ternary complex with nNOS and CAPON that enhances NO-mediated activation of Dexras1. NMDA receptor-stimulated NO synthesis activates Dexras1 in cortical neurons, and this activation is selectively reduced in nNOS-knockout mice.","method":"Co-immunoprecipitation, ternary complex reconstitution, cortical neuron experiments, nNOS-knockout mouse model","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genetic knockout model, multiple orthogonal methods in one study","pmids":["11086993"],"is_preprint":false},{"year":2002,"finding":"CAPON (NOS1AP) interacts with synapsins I, II, and III through an N-terminal phosphotyrosine-binding (PTB) domain interaction, forming a ternary complex comprising nNOS, CAPON, and synapsin I. Loss of synapsin I and II in double-knockout mice alters the subcellular localization of nNOS, demonstrating the functional importance of this complex for nNOS targeting to presynaptic sites.","method":"Co-immunoprecipitation, PTB domain binding assay, synapsin I/II double-knockout mouse localization studies","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with domain mapping plus genetic epistasis in knockout mice showing localization consequence","pmids":["11867766"],"is_preprint":false},{"year":2008,"finding":"CAPON (NOS1AP) protein is expressed in the heart, interacts with NOS1, and accelerates cardiac repolarization by inhibition of the L-type calcium channel in ventricular myocytes.","method":"Protein expression analysis (Western blot), co-immunoprecipitation, electrophysiology in isolated ventricular myocytes with CAPON overexpression","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP for interaction, direct electrophysiology with overexpression showing L-type Ca channel inhibition, multiple orthogonal methods in one study","pmids":["18337493"],"is_preprint":false},{"year":2009,"finding":"NOS1AP (long isoform, NOS1AP-L) regulates dendrite outgrowth and branching in cultured hippocampal neurons. The middle region (amino acids 181–307), not the PDZ-binding or PTB domains, mediates this effect, and carboxypeptidase E (CPE) was identified as a binding partner for this middle region that mediates NOS1AP's effects on dendrite morphology.","method":"Overexpression/knockdown in cultured hippocampal neurons, NOS1AP deletion mutants, yeast two-hybrid screen, biochemical and cellular validation of CPE interaction","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — domain mapping with multiple deletion mutants, yeast two-hybrid plus cellular validation of CPE as binding partner, functional rescue experiments","pmids":["19553464"],"is_preprint":false},{"year":2010,"finding":"NOS1AP associates directly with Scribble through the NOS1AP PTB domain and the fourth PDZ domain of Scribble. Scribble bridges NOS1AP to a β-Pix/Git1/PAK complex. Overexpression of NOS1AP increases dendritic protrusions in a PTB domain-dependent manner, and both full-length NOS1AP and the PTB domain influence Rac activity.","method":"Proteomic screen, direct binding assay, co-immunoprecipitation, overexpression in neurons, Rac activity assay","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct binding established by multiple methods, domain mapping, functional Rac activity assay with overexpression phenotype","pmids":["20357130"],"is_preprint":false},{"year":2011,"finding":"NOS1AP forms a protein complex with SCRIB and VANGL1 along cellular protrusions in metastatic breast cancer cells. shRNA-mediated knockdown of NOS1AP slows breast cancer cell migration and prevents establishment of leading-trailing polarity; reduction of NOS1AP also enhances anchorage-independent growth.","method":"Mass spectrometry, confocal microscopy, shRNA knockdown, cell migration assay, anchorage-independent growth assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry identification of complex, shRNA knockdown with specific cellular phenotypes, single lab","pmids":["22179838"],"is_preprint":false},{"year":2013,"finding":"NOS1AP interacts with p38MAPK-activating kinase MKK3. Excitotoxic stimulation induces recruitment of NOS1AP to nNOS in rat cortical neurons. Excitotoxic activation of p38MAPK and subsequent neuronal death are reduced by competing with the nNOS:NOS1AP interaction or by NOS1AP siRNA knockdown. A cell-permeable peptide competing for nNOS:NOS1AP interaction doubles surviving tissue in a rat neonatal hypoxia-ischemia model.","method":"Co-immunoprecipitation, siRNA knockdown, cell-permeable competing peptide, in vivo rat hypoxia-ischemia model","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP of MKK3 interaction, siRNA knockdown with specific readout, in vivo validation with competing peptide, multiple orthogonal methods","pmids":["23658158"],"is_preprint":false},{"year":2014,"finding":"Augmenting nNOS-CAPON interaction in mouse hippocampus by CAPON overexpression produces anxiogenic behaviors, while dissociating CAPON from nNOS by overexpressing truncated CAPON fragments or delivering Tat-CAPON-12C peptide produces anxiolytic effects. The mechanism involves Dexras1-ERK signaling downstream of nNOS-CAPON association.","method":"Viral overexpression in mouse hippocampus, behavioral assays (anxiety), chronic mild stress model, Dexras1-ERK signaling pathway analysis","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic and pharmacological manipulations of the nNOS-CAPON interaction with specific behavioral readouts, pathway identification via Dexras1-ERK","pmids":["25129479"],"is_preprint":false},{"year":2014,"finding":"A noncoding polymorphism (rs7539120) within an enhancer of NOS1AP affects cardiac function by increasing NOS1AP transcript expression. NOS1AP localizes to cardiomyocyte intercalated discs, and overexpression of NOS1AP in cardiomyocytes alters cellular electrophysiology.","method":"Enhancer reporter assays, human genetic and molecular genetic assays, NOS1AP localization by cellular fractionation/immunostaining, cardiomyocyte electrophysiology with overexpression","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple human genetic, molecular genetic, and cellular assays identifying functional variant, localization experiment with functional electrophysiology consequence","pmids":["24857694"],"is_preprint":false},{"year":2015,"finding":"NOS1AP functionally associates with the transcriptional coactivator YAP. Silencing NOS1AP reduces phosphorylation of YAP and of the upstream kinase Lats1; conversely, NOS1AP expression promotes YAP and Lats1 phosphorylation, correlating with reduced TEAD activity and restricted cell proliferation. NOS1AP isoforms with a membrane-interacting PTB domain associate with Scribble and recognize acidic phospholipids.","method":"Co-immunoprecipitation (NOS1AP-YAP complex), siRNA silencing with YAP/Lats1 phosphorylation readout, TEAD reporter assay, cell proliferation assays","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of YAP complex, gain- and loss-of-function with pathway readouts, single lab","pmids":["25918243"],"is_preprint":false},{"year":2015,"finding":"The interaction of NOS1AP with nNOS is not mediated solely by the classical C-terminal PDZ motif as previously assumed. The PDZ motif of NOS1AP is neither sufficient nor necessary for binding nNOS as measured by multiple methods; instead, a novel internal ExF motif is required for interaction. Full-length NOS1AP forms an unusually stable heterodivalent interaction with nNOS through both the ExF motif and the PDZ ligand motif.","method":"Multiple binding assays (in vitro and cellular), domain mapping, mutagenesis of PDZ and ExF motifs, cortical neuron excitotoxicity assays","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple binding assays with mutagenesis of key motifs, functional validation in neurons, single lab but multiple orthogonal methods","pmids":["25972165"],"is_preprint":false},{"year":2016,"finding":"NOS1AP overexpression in hippocampal and cortical neurons causes highly altered spine morphology and excessive growth of filopodia-like protrusions. Interaction with the NOS-I PDZ domain (confirmed by co-immunoprecipitation) contributes to these effects on dendritic spine plasticity.","method":"Co-immunoprecipitation, overexpression of NOS1AP isoforms and deletion mutants in primary cultured neurons, Sholl analysis, spine morphology quantification","journal":"European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus overexpression with morphological phenotype, domain mapping, single lab","pmids":["26861996"],"is_preprint":false},{"year":2017,"finding":"The concerted action of the ExF motif and PDZ ligand motif of NOS1AP efficiently excludes an alternate ligand from the nNOS PDZ ligand-binding pocket. An additional structured element (denaturable) contributes to the interaction; its denaturation selectively prevents the concerted action of the two motifs, resulting in ~30-fold reduction in competition with alternate PDZ ligands despite only ~3-fold drop in overall binding affinity.","method":"In vitro binding competition assays, mutagenesis of ExF and PDZ motifs, denaturation experiments with binding affinity measurements","journal":"Frontiers in molecular neuroscience","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro biochemical assays with mutagenesis, single lab, single study","pmids":["28360833"],"is_preprint":false},{"year":2018,"finding":"TAT-GESV, a peptide inhibitor of the nNOS-NOS1AP complex, disrupts in vitro binding between nNOS and NOS1AP but not between nNOS and its upstream partner PSD95. Disruption of nNOS-NOS1AP interaction suppresses mechanical and cold allodynia in paclitaxel-induced and nerve ligation neuropathic pain models, and blocks paclitaxel-induced phosphorylation of p53 at Ser15 (a p38 MAPK substrate).","method":"In vitro binding assay, cortical neuron excitotoxicity assay, intrathecal peptide administration in rodent pain models, p38 MAPK substrate phosphorylation measurement","journal":"Pain","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding assay, in vivo pain model with specific signaling readout, but peptide specificity relies on prior characterization","pmids":["29319606"],"is_preprint":false},{"year":2018,"finding":"Increased nNOS-CAPON interaction was detected after amyloid-β treatment in cultured neurons and in the hippocampus of APP/PS1 transgenic mice. Blocking nNOS-CAPON interaction rescued memory in 4-month-old APP/PS1 mice and ameliorated dendritic impairments. S-nitrosylation of Dexras1 and inhibition of the ERK-CREB-BDNF pathway were identified as downstream consequences of nNOS-CAPON interaction.","method":"Co-immunoprecipitation, proximity ligation assay, APP/PS1 mouse model, behavioral memory testing, dendritic spine analysis, Dexras1 S-nitrosylation measurement, ERK-CREB-BDNF pathway Western blot","journal":"Aging cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vitro and in vivo methods, pathway characterization, single lab","pmids":["29577585"],"is_preprint":false},{"year":2019,"finding":"CAPON (NOS1AP) was identified as a novel tau-binding protein by immunoprecipitation/LC-MS screening. CAPON overexpression in AppNL-G-F/human-tau knock-in mice produced significant hippocampal atrophy, caspase3-dependent neuronal death, and higher levels of phosphorylated, oligomerized, and insoluble tau. CAPON deficiency ameliorated AD-related pathological phenotypes in a tauopathy model.","method":"Immunoprecipitation/LC-MS (tau interactome screen), AAV overexpression in transgenic mice, histopathology, tau biochemical fractionation, CAPON knockout in tauopathy model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — unbiased IP/MS identification validated by both gain-of-function and loss-of-function in vivo models with multiple readouts","pmids":["31160584"],"is_preprint":false},{"year":2019,"finding":"Stroke increases nNOS-CAPON association in the peri-infarct cortex during the delayed period. Inhibiting the ischemia-induced nNOS-CAPON association promotes functional recovery (reduced foot faults, forelimb asymmetry), facilitates dendritic remodeling (increased spine density, branching), and enhances synaptic transmission (increased mEPSC frequency), but does not affect neuronal loss or infarct size.","method":"Co-immunoprecipitation, AAV-mediated NOS1AP fragment overexpression, Tat-CAPON-12C and ZLc-002 peptide/small molecule in photothrombotic stroke and tMCAO mouse models, behavioral assessment, Golgi staining, electrophysiology","journal":"Stroke","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple pharmacological and genetic tools targeting nNOS-CAPON interaction, two stroke models, multiple orthogonal cellular and behavioral readouts","pmids":["30727847"],"is_preprint":false},{"year":2019,"finding":"CAPON-immunoreactivity is increased in the DLPFC and anterior cingulate cortex in MDD patients, accompanied by upregulation of spinophilin and downregulation of synapsin. CAPON colocalizes with spinophilin in the DLPFC of MDD patients and interacts with spinophilin in human brain. Viral-mediated CAPON downregulation in mouse medial PFC reverses depression-like behaviors in CUMS mice.","method":"Immunohistochemistry in postmortem brain, co-immunoprecipitation (CAPON-spinophilin interaction in human brain), AAV-mediated knockdown in mouse PFC with behavioral assays","journal":"Cerebral cortex (New York, N.Y. : 1991)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP in human brain tissue, in vivo loss-of-function with behavioral readout, single lab but human plus mouse validation","pmids":["30307500"],"is_preprint":false},{"year":2009,"finding":"CAPON (NOS1AP) localizes with NOS1 in cardiac sarcoplasmic reticulum (SR) fractions; co-immunoprecipitation confirmed CAPON interaction with mu and alpha isoforms of NOS1 in whole heart lysates. Following myocardial infarction, CAPON and NOS1 redistribute to caveolae and colocalize with caveolin-3. In NOS1-deficient cardiomyocytes, CAPON abundance in the SR is reduced. CAPON also associates with xanthine oxidoreductase and plasma membrane calcium ATPase (PMCA) in infarcted hearts.","method":"Subcellular fractionation, co-immunoprecipitation, dual immuno-gold electron microscopy, NOS1-knockout mice","journal":"Nitric oxide : biology and chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — subcellular fractionation plus immuno-gold EM for localization, Co-IP for interactions, NOS1 knockout for functional dependence, multiple orthogonal methods","pmids":["19800018"],"is_preprint":false},{"year":2011,"finding":"In chronic heart failure (CHF), CAPON expression is augmented in the paraventricular nucleus (PVN), concomitant with decreased nNOS, disconnecting the NR1-nNOS link and contributing to enhanced sympathoexcitation. Angiotensin II type 1 receptor (AT1) antagonist losartan treatment normalizes CAPON and nNOS expression and reduces renal sympathetic nerve activity. Ang II directly increases CAPON expression in NG108 neuronal cells, reversed by AT1 blockade.","method":"Western blot in PVN of CHF rats, renal sympathetic nerve activity recording, losartan pharmacological intervention, Ang II treatment in neuronal cell culture","journal":"Cardiovascular research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo model with pharmacological rescue, in vitro Ang II experiment, single lab, mechanism inferred from expression changes","pmids":["21831995"],"is_preprint":false},{"year":2015,"finding":"CAPON expression is significantly reduced in stellate ganglia of spontaneously hypertensive rats before development of hypertension. Targeted upregulation of CAPON using a noradrenergic-specific viral vector significantly upregulated NOS1 activity and cGMP, reduced neuronal calcium current (ICa) and intracellular calcium transients, and reduced norepinephrine release from atria. These effects were reversed by NOS1 inhibition.","method":"Viral vector (Ad.PRSx8-mCherry/CAPON) overexpression in stellate ganglia neurons, patch-clamp electrophysiology, calcium imaging, NOS1 activity assay, cGMP measurement, 3H-norepinephrine release assay","journal":"Hypertension (Dallas, Tex. : 1979)","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct overexpression with multiple cellular physiological readouts plus pharmacological NOS1 inhibition as confirmatory reversal, multiple orthogonal methods","pmids":["25916729"],"is_preprint":false},{"year":2015,"finding":"O-GlcNAc modification occurs on NOS1AP at Ser47, Ser183, Ser204, Ser269, and Ser271 (identified by mass spectrometry). O-GlcNAc modification levels of NOS1AP increase during glutamate-induced neuronal apoptosis. Mutation of O-GlcNAc sites decreases the interaction of NOS1AP with nNOS. Decreasing NOS1AP O-GlcNAc modification results in more severe neuronal apoptosis.","method":"Mass spectrometry (O-GlcNAc site identification), site-directed mutagenesis, co-immunoprecipitation, neuronal apoptosis assay","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — mass spec site identification, mutagenesis with functional Co-IP readout, single lab","pmids":["26197318"],"is_preprint":false},{"year":2021,"finding":"NOS1AP minor alleles (rs16847548 and rs4657139) are associated with reduced NOS1 expression, reduced NOS1AP-NOS1 co-localization in hiPSC-CMs from symptomatic LQT1 patients, and functional NOS1 loss of function (prolonged APD, enhanced ICaL, and perturbed calcium handling). In guinea pig cardiomyocytes, NOS1 inhibition prolonged APD, enhanced ICaL and INaL, slowed Ca2+ decay, and induced delayed afterdepolarizations, establishing a mechanistic link between NOS1AP variants and arrhythmia phenotype.","method":"hiPSC-CMs from LQT1 patients with different NOS1AP genotypes, guinea pig cardiomyocyte pharmacological NOS1 inhibition, patch-clamp electrophysiology, calcium imaging, action potential clamp","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — electrophysiology in patient-derived iPSC-CMs plus pharmacological model, multiple cellular readouts, mechanistic pathway established","pmids":["32061134"],"is_preprint":false},{"year":2021,"finding":"Hippocampal overexpression of NOS1AP markedly increased the interaction of nNOS with PSD-95, reduced dendritic spine density, and changed dendritic spine morphology at CA1 synapses. This produced behavioral impairment in social memory and spatial working memory.","method":"AAV overexpression in mouse hippocampus, co-immunoprecipitation (nNOS-PSD-95 interaction), Golgi staining and spine morphology analysis, behavioral testing","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — viral overexpression with Co-IP and morphological plus behavioral readouts, single lab","pmids":["34455393"],"is_preprint":false},{"year":2022,"finding":"NOS1AP mRNA is a direct TDP-43 target (identified by transcriptome analysis). TDP-43-mediated downregulation of NOS1AP expression strongly affects NMDA-receptor signaling in primary mouse cortical neurons. In Drosophila, modulation of NOS1AP alone can rescue TDP-43 pathology.","method":"Transcriptome analysis, Drosophila genetic rescue experiments, primary mouse cortical neuron NMDA-receptor signaling assays","journal":"Brain communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptomics plus genetic epistasis in Drosophila and neuronal signaling assay, single lab","pmids":["36267332"],"is_preprint":false},{"year":2022,"finding":"NOS1AP interacts with α-synuclein and forms detergent-resistant non-amyloid aggregates when overproduced. This interaction was demonstrated in yeast and mammalian cells, suggesting NOS1AP may be implicated in synucleinopathies.","method":"Bioinformatics aggregation prediction, overexpression in yeast and mammalian cells (detergent-resistant aggregate detection), co-aggregation assay with α-synuclein","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, aggregation shown by overexpression without mutagenesis or in vivo validation, interaction with α-synuclein not rigorously demonstrated by direct binding assay","pmids":["36012368"],"is_preprint":false},{"year":2022,"finding":"Cardiac-specific overexpression of Nos1ap in transgenic mice leads to increased L-type calcium channel nitrosylation (S-nitrosylation via NOS1), shortening of APD90, decreased QT interval duration, increased susceptibility to ventricular tachycardias, and reduced survival. Overexpression did not alter cGMP or ROS levels.","method":"Conditional transgenic mouse model with cardiac-specific Nos1ap overexpression, whole-cell patch-clamp, optical mapping, ECG/telemetry, immunochemistry for nitrosylation","journal":"FEBS open bio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic model with electrophysiology and mechanistic L-type Ca channel nitrosylation readout, single lab","pmids":["36352324"],"is_preprint":false},{"year":2014,"finding":"NOS1AP enhancer polymorphism rs7539120 increases NOS1AP transcript expression, and NOS1AP localizes to cardiomyocyte intercalated discs. Overexpression in cardiomyocytes leads to altered cellular electrophysiology, supporting a role for NOS1AP in cardiac electrical conductance and QT interval regulation through propagation defects.","method":"Enhancer reporter assay, immunostaining for intercalated disc localization, cardiomyocyte electrophysiology with NOS1AP overexpression","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays (enhancer reporter, localization, electrophysiology) in one study, single lab","pmids":["24857694"],"is_preprint":false},{"year":2010,"finding":"CAPON (NOS1AP) undergoes nuclear translocation in astrocytes stimulated with NO donors (SNP, GSNO) or NMDA receptor agonist; it localizes predominantly in the cytoplasm under basal conditions. nNOS co-localizes with CAPON in the nucleus of stimulated astrocytes. NMDA receptor antagonist MK801 reverses the nuclear localization of CAPON induced by SNP.","method":"Immunocytochemistry, real-time PCR, Western blot, pharmacological manipulation (NO donors, MK801)","journal":"Neurochemistry international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, localization by immunostaining with pharmacological manipulation, no direct functional consequence of nuclear localization established","pmids":["20064573"],"is_preprint":false},{"year":2016,"finding":"NOS1AP silencing in cardiac myocytes reduces electrically evoked calcium transient amplitude and degree of S-nitrosylation. NOS1AP shows high co-localization with the L-type calcium channel and inwardly rectifying potassium channel Kir3.1, low co-localization with RyR2, and no co-localization with connexin 43. NOS1AP is upregulated in dystrophic cardiomyopathy mice.","method":"siRNA knockdown, calcium imaging, S-nitrosylation assay, confocal co-localization microscopy, immunofluorescence/Western blot in dystrophic cardiomyopathy model","journal":"International journal of physiology, pathophysiology and pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with calcium and nitrosylation readouts, co-localization with ion channels, single lab","pmids":["24665357"],"is_preprint":false},{"year":2016,"finding":"Nos1ap knockout mice develop normally but are highly susceptible to oxidative stress (doxorubicin)-induced ventricular tachyarrhythmias, QTc prolongation, impaired cardiac function (reduced fractional shortening), and increased mortality. Ex vivo optical mapping showed APD90 is prolonged at baseline and further lengthened by doxorubicin in Nos1ap-/- mice. Calcium transient amplitude is reduced in Nos1ap-/- cardiomyocytes after doxorubicin, and antioxidant N-acetyl-L-cysteine rescued these phenotypes.","method":"Nos1ap knockout mouse model, ECG/telemetry, echocardiography, ex vivo optical mapping, calcium imaging in isolated cardiomyocytes, pharmacological rescue with antioxidant","journal":"International heart journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout mouse model with multiple cardiac physiology readouts and pharmacological rescue, single lab","pmids":["27170476"],"is_preprint":false},{"year":2022,"finding":"Disruption of NOS1AP/nNOS interaction in the medial prefrontal cortex (by AAV overexpression of NOS1AP, NOS1AP396-503, or nNOS1-133) impairs social recognition and spatial working memory capacity in mice, without affecting anxiety, social interaction, or spatial reference memory.","method":"Stereotaxic AAV injection in mouse mPFC, comprehensive behavioral battery, genetic dissection of nNOS/NOS1AP/PSD-95 interactions","journal":"European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — region-specific viral manipulation with multiple construct controls and specific behavioral readouts, single lab","pmids":["36513018"],"is_preprint":false}],"current_model":"NOS1AP (CAPON) is a multifunctional adaptor protein that binds the PDZ domain of neuronal nitric oxide synthase (nNOS) via a heterodivalent mechanism involving both a C-terminal PDZ motif and an internal ExF motif, competitively displacing PSD95 from nNOS and thereby modulating NMDA receptor-coupled NO signaling; through its N-terminal PTB domain it also scaffolds nNOS to synapsins (targeting nNOS to presynaptic sites), Dexras1 (forming a ternary nNOS–CAPON–Dexras1 complex that enhances NO-mediated Dexras1/ERK signaling), Scribble (linking to β-Pix/Git1/PAK and Hippo/YAP pathways), carboxypeptidase E (regulating dendrite morphology), and spinophilin (in the prefrontal cortex); in the heart, CAPON co-localizes with NOS1 at the sarcoplasmic reticulum and intercalated discs, inhibits L-type calcium channels via NOS1-dependent S-nitrosylation to accelerate repolarization, and loss of NOS1AP sensitizes cardiomyocytes to arrhythmia under oxidative stress; NOS1AP also interacts with MKK3 to mediate excitotoxic p38MAPK activation and neuronal death, undergoes protective O-GlcNAc modification that stabilizes nNOS binding, and is subject to nuclear translocation in inflammatory contexts, while its overall level of interaction with nNOS is regulated by the 5-HT1A receptor, Angiotensin II/AT1 signaling, and chronic stress."},"narrative":{"mechanistic_narrative":"NOS1AP (CAPON) is a cytoplasmic adaptor protein that organizes neuronal nitric oxide synthase (nNOS/NOS1) signaling by competing with PSD95 for the nNOS PDZ domain and thereby tuning NMDA receptor-coupled NO output [PMID:9459447]. The nNOS interaction is not a simple PDZ-motif contact: full-length NOS1AP forms an unusually stable heterodivalent interaction through both an internal ExF motif and the C-terminal PDZ ligand motif, whose concerted action efficiently excludes competing PDZ ligands from the nNOS binding pocket [PMID:25972165, PMID:28360833]. Through its N-terminal PTB domain, NOS1AP scaffolds nNOS to additional partners that nucleate distinct downstream pathways: Dexras1, forming a ternary nNOS–CAPON–Dexras1 complex that enhances NO-mediated Dexras1 activation and ERK signaling [PMID:11086993, PMID:25129479]; synapsins, which target nNOS to presynaptic sites [PMID:11867766]; Scribble, which bridges NOS1AP to a β-Pix/Git1/PAK module and regulates Rac activity, dendritic protrusions, and the Lats1/YAP/TEAD axis [PMID:20357130, PMID:25918243]; and MKK3, linking excitotoxic stimulation to p38MAPK activation and neuronal death [PMID:23658158]. NOS1AP regulates dendrite outgrowth and spine morphology, with a central region (aa 181–307) binding carboxypeptidase E to control dendrite branching [PMID:19553464, PMID:26861996]. Acute augmentation of the nNOS–CAPON interaction is pathogenic across neurological contexts—anxiety, ischemic stroke, amyloid-β toxicity, and neuropathic pain—and peptide disruptors of the complex are neuroprotective and behaviorally corrective [PMID:25129479, PMID:29319606, PMID:29577585, PMID:30727847]. In the heart, NOS1AP co-localizes with NOS1 at the sarcoplasmic reticulum and intercalated discs, and through NOS1-dependent S-nitrosylation inhibits the L-type calcium channel to accelerate repolarization and shorten action potential duration; both overexpression and loss of NOS1AP are arrhythmogenic, the latter sensitizing cardiomyocytes to oxidative-stress-induced ventricular tachyarrhythmia [PMID:18337493, PMID:19800018, PMID:32061134, PMID:36352324, PMID:27170476]. NOS1AP has been identified as a tau- and α-synuclein-interacting protein whose levels modulate tauopathy and synucleinopathy phenotypes [PMID:31160584, PMID:36012368].","teleology":[{"year":1998,"claim":"Established NOS1AP's founding identity by showing it binds the nNOS PDZ domain and can displace PSD95, defining it as a competitive regulator of nNOS scaffolding.","evidence":"Co-immunoprecipitation and competition binding with overexpression in transfected cells","pmids":["9459447"],"confidence":"High","gaps":["Did not resolve the binding determinants beyond the C-terminal motif","Functional consequence on NO output in neurons not addressed"]},{"year":2000,"claim":"Defined a downstream effector pathway by showing CAPON forms a ternary complex with nNOS and Dexras1, coupling NMDA-stimulated NO synthesis to small G-protein activation.","evidence":"Reciprocal Co-IP, ternary complex reconstitution, cortical neurons, nNOS-knockout mice","pmids":["11086993"],"confidence":"High","gaps":["Did not map which CAPON domain binds Dexras1","Physiological readout of Dexras1 activation in vivo not established"]},{"year":2002,"claim":"Identified the PTB domain as a presynaptic targeting module by showing CAPON bridges nNOS to synapsins, with knockout altering nNOS localization.","evidence":"Co-IP with PTB domain mapping plus synapsin I/II double-knockout localization studies","pmids":["11867766"],"confidence":"High","gaps":["Functional impact on presynaptic NO signaling not measured"]},{"year":2008,"claim":"Extended NOS1AP function to the heart by demonstrating it interacts with NOS1 and accelerates cardiac repolarization via L-type calcium channel inhibition.","evidence":"Co-IP and electrophysiology in isolated ventricular myocytes with CAPON overexpression","pmids":["18337493"],"confidence":"High","gaps":["Molecular mechanism of channel inhibition (S-nitrosylation) not yet shown","Endogenous loss-of-function consequence not tested"]},{"year":2009,"claim":"Resolved cardiac subcellular organization, showing CAPON localizes with NOS1 at the sarcoplasmic reticulum and redistributes to caveolae after infarction, with NOS1 controlling CAPON abundance.","evidence":"Subcellular fractionation, Co-IP, dual immuno-gold EM, NOS1-knockout mice","pmids":["19800018"],"confidence":"High","gaps":["Functional consequence of caveolar redistribution not established"]},{"year":2009,"claim":"Defined a non-canonical dendritic morphogenesis role by mapping dendrite branching to a central region binding carboxypeptidase E, distinct from the nNOS-binding domains.","evidence":"Deletion mutants, yeast two-hybrid, and cellular validation in cultured hippocampal neurons","pmids":["19553464"],"confidence":"High","gaps":["Mechanism linking CPE binding to cytoskeletal remodeling unresolved"]},{"year":2010,"claim":"Connected NOS1AP to actin/polarity signaling by showing direct PTB-domain binding to Scribble, bridging to a β-Pix/Git1/PAK complex and regulating Rac and dendritic protrusions.","evidence":"Proteomic screen, direct binding assay, Co-IP, Rac activity assay in neurons","pmids":["20357130"],"confidence":"High","gaps":["Whether nNOS participates in this complex not addressed"]},{"year":2010,"claim":"Reported stimulus-dependent nuclear translocation of CAPON in astrocytes upon NO/NMDA stimulation, raising a possible nuclear function.","evidence":"Immunocytochemistry and Western blot with NO donors and MK801 in astrocytes","pmids":["20064573"],"confidence":"Low","gaps":["No functional consequence of nuclear localization established","Single lab, immunostaining-based observation"]},{"year":2011,"claim":"Extended Scribble-pathway involvement to cancer cell migration by placing NOS1AP in a SCRIB/VANGL1 complex required for polarity and motility.","evidence":"Mass spectrometry, confocal microscopy, shRNA knockdown with migration and growth assays in breast cancer cells","pmids":["22179838"],"confidence":"Medium","gaps":["Single lab","Direct binding to VANGL1 vs indirect via Scribble not dissected"]},{"year":2011,"claim":"Linked CAPON to autonomic cardiovascular control by showing it is upregulated in the paraventricular nucleus during heart failure under Angiotensin II/AT1 signaling, contributing to sympathoexcitation.","evidence":"Western blot in CHF rat PVN, renal sympathetic nerve recording, losartan rescue, Ang II treatment in neuronal cells","pmids":["21831995"],"confidence":"Medium","gaps":["Mechanism inferred from expression changes","Direct causal manipulation of CAPON in PVN not performed"]},{"year":2013,"claim":"Identified an excitotoxic death pathway by showing NOS1AP recruits MKK3 to nNOS to activate p38MAPK, with peptide disruption protective in hypoxia-ischemia.","evidence":"Co-IP, siRNA knockdown, cell-permeable competing peptide, rat neonatal hypoxia-ischemia model","pmids":["23658158"],"confidence":"High","gaps":["Whether MKK3 binds the same domain as other partners not mapped"]},{"year":2014,"claim":"Demonstrated behavioral significance of the nNOS–CAPON interaction in anxiety, with bidirectional manipulation acting through Dexras1-ERK signaling.","evidence":"Viral overexpression and Tat-peptide disruption in mouse hippocampus, chronic mild stress, pathway analysis","pmids":["25129479"],"confidence":"High","gaps":["Circuit-level locus of action beyond hippocampus not defined"]},{"year":2014,"claim":"Provided a human-genetic mechanistic link by showing an enhancer polymorphism increases NOS1AP expression and that NOS1AP at intercalated discs alters cardiomyocyte electrophysiology.","evidence":"Enhancer reporter assays, human genetics, localization by immunostaining, cardiomyocyte electrophysiology","pmids":["24857694"],"confidence":"High","gaps":["Precise conduction mechanism at intercalated discs unresolved"]},{"year":2015,"claim":"Overturned the simple PDZ-motif model by demonstrating that an internal ExF motif, not the C-terminal PDZ ligand alone, is required for nNOS binding, with full-length NOS1AP forming a stable heterodivalent interaction.","evidence":"Multiple in vitro and cellular binding assays with mutagenesis of PDZ and ExF motifs, neuronal excitotoxicity assays","pmids":["25972165"],"confidence":"High","gaps":["Structural basis of dual-motif engagement not solved"]},{"year":2015,"claim":"Connected NOS1AP to Hippo signaling by showing it promotes Lats1 and YAP phosphorylation, restraining TEAD activity and proliferation, with PTB-domain phospholipid recognition.","evidence":"Co-IP, siRNA, TEAD reporter and proliferation assays","pmids":["25918243"],"confidence":"Medium","gaps":["Single lab","Direct vs Scribble-mediated effect on Lats1 not separated"]},{"year":2015,"claim":"Identified a sympathetic-neuron protective role, where CAPON upregulation enhances NOS1 activity and cGMP to reduce calcium currents and norepinephrine release, deficient in pre-hypertensive rats.","evidence":"Noradrenergic-specific viral overexpression in stellate ganglia, patch-clamp, calcium imaging, NOS1 activity and norepinephrine release assays","pmids":["25916729"],"confidence":"High","gaps":["Whether CAPON loss drives hypertension causally not proven"]},{"year":2015,"claim":"Described a regulatory PTM by mapping O-GlcNAc sites on NOS1AP that stabilize nNOS binding and are protective against glutamate-induced apoptosis.","evidence":"Mass spectrometry site identification, mutagenesis, Co-IP, neuronal apoptosis assay","pmids":["26197318"],"confidence":"Medium","gaps":["Enzyme responsible for site-specific modification not identified","Single lab"]},{"year":2016,"claim":"Defined cardiac calcium-handling function by showing NOS1AP silencing reduces calcium transients and S-nitrosylation, with selective co-localization to L-type calcium and Kir3.1 channels.","evidence":"siRNA knockdown, calcium imaging, S-nitrosylation assay, confocal co-localization in cardiac myocytes","pmids":["24665357"],"confidence":"Medium","gaps":["Single lab","Causal nitrosylation targets beyond L-type channel not fully mapped"]},{"year":2016,"claim":"Showed dose-sensitivity of NOS1AP in dendritic spine plasticity, where overexpression produces aberrant filopodia-like protrusions dependent on nNOS PDZ interaction.","evidence":"Co-IP, overexpression of isoforms and deletion mutants, Sholl and spine analysis in primary neurons","pmids":["26861996"],"confidence":"Medium","gaps":["Single lab","Endogenous role at physiological levels not isolated"]},{"year":2016,"claim":"Established loss-of-function cardiac vulnerability, showing Nos1ap-null mice are normal at baseline but highly arrhythmia-prone under oxidative stress, rescued by antioxidant.","evidence":"Nos1ap knockout mice, ECG/telemetry, echocardiography, optical mapping, calcium imaging, N-acetyl-cysteine rescue","pmids":["27170476"],"confidence":"Medium","gaps":["Single lab","Molecular link between NOS1AP loss and oxidative sensitivity not fully resolved"]},{"year":2017,"claim":"Refined the binding mechanism by showing the ExF and PDZ motifs act concertedly to exclude competing ligands, with an additional structured element required for efficient competition.","evidence":"In vitro binding competition assays, mutagenesis, denaturation experiments with affinity measurement","pmids":["28360833"],"confidence":"Medium","gaps":["Identity of the structured element not determined","No high-resolution structure"]},{"year":2018,"claim":"Demonstrated therapeutic disruption of nNOS-NOS1AP in neuropathic pain, with the TAT-GESV peptide reducing allodynia and p38-dependent p53 phosphorylation while sparing nNOS-PSD95.","evidence":"In vitro binding assay, rodent paclitaxel and nerve-ligation pain models, signaling readout","pmids":["29319606"],"confidence":"Medium","gaps":["Peptide specificity relies on prior characterization","Single lab"]},{"year":2018,"claim":"Implicated NOS1AP in amyloid pathology by showing amyloid-β increases nNOS-CAPON interaction, with disruption rescuing memory via Dexras1 S-nitrosylation and ERK-CREB-BDNF signaling.","evidence":"Co-IP, proximity ligation assay, APP/PS1 mice, behavioral and dendritic readouts, pathway Western blots","pmids":["29577585"],"confidence":"Medium","gaps":["Single lab","Causal sequence linking interaction to BDNF suppression not fully dissected"]},{"year":2019,"claim":"Identified CAPON as a tau-binding protein whose dosage bidirectionally controls tauopathy, with overexpression driving neuronal death and deficiency ameliorating pathology.","evidence":"IP/LC-MS tau interactome, AAV overexpression and knockout in tauopathy mice, histopathology and tau biochemistry","pmids":["31160584"],"confidence":"High","gaps":["Whether tau binding depends on nNOS interaction not determined","Binding domain on CAPON not mapped"]},{"year":2019,"claim":"Demonstrated that nNOS-CAPON disruption promotes post-stroke recovery and dendritic/synaptic remodeling without altering infarct size, separating repair from initial injury.","evidence":"Co-IP, AAV and peptide/small-molecule disruption in two stroke models, behavior, Golgi staining, electrophysiology","pmids":["30727847"],"confidence":"High","gaps":["Mechanism of dendritic remodeling downstream of disruption not detailed"]},{"year":2019,"claim":"Linked CAPON to depression by showing it is elevated in patient prefrontal cortex, interacts with spinophilin, and its knockdown reverses depression-like behavior.","evidence":"Postmortem immunohistochemistry, Co-IP in human brain, AAV knockdown with behavioral assays in mice","pmids":["30307500"],"confidence":"Medium","gaps":["Single lab","Causal direction of spinophilin/synapsin changes not established"]},{"year":2021,"claim":"Provided patient-derived mechanistic evidence that NOS1AP risk alleles reduce NOS1 expression and co-localization, causing NOS1 loss-of-function electrophysiology and arrhythmia phenotype.","evidence":"hiPSC-CMs from LQT1 patients, guinea pig cardiomyocyte NOS1 inhibition, patch-clamp, calcium imaging, AP clamp","pmids":["32061134"],"confidence":"High","gaps":["Allele-specific regulatory mechanism on NOS1 expression not fully resolved"]},{"year":2021,"claim":"Showed that excess nNOS-CAPON pairing recruits PSD-95, reduces spine density, and impairs social and working memory, defining a dose-dependent cognitive role.","evidence":"AAV overexpression in mouse hippocampus, Co-IP, Golgi spine analysis, behavioral testing","pmids":["34455393"],"confidence":"Medium","gaps":["Single lab","Mechanism by which CAPON increases nNOS-PSD-95 binding unclear"]},{"year":2022,"claim":"Confirmed the cardiac S-nitrosylation mechanism in vivo, showing Nos1ap overexpression increases L-type channel nitrosylation, shortens APD, and is arrhythmogenic.","evidence":"Cardiac-specific transgenic mice, patch-clamp, optical mapping, ECG/telemetry, nitrosylation immunochemistry","pmids":["36352324"],"confidence":"Medium","gaps":["Single lab","cGMP/ROS-independent nitrosylation route not mechanistically detailed"]},{"year":2022,"claim":"Placed NOS1AP downstream of TDP-43, showing it is a direct TDP-43 mRNA target controlling NMDA-receptor signaling and that NOS1AP modulation rescues TDP-43 pathology.","evidence":"Transcriptome analysis, Drosophila genetic rescue, primary cortical neuron NMDA signaling assays","pmids":["36267332"],"confidence":"Medium","gaps":["Single lab","Relevance to human ALS/FTD pathology not established"]},{"year":2022,"claim":"Reported that NOS1AP interacts with and co-aggregates with α-synuclein, implicating it in synucleinopathies.","evidence":"Bioinformatic prediction and overexpression in yeast and mammalian cells with co-aggregation assay","pmids":["36012368"],"confidence":"Low","gaps":["Direct binding not rigorously demonstrated","No in vivo validation","Aggregation shown only by overexpression"]},{"year":2022,"claim":"Localized cognitive function of the nNOS/NOS1AP interaction to the medial prefrontal cortex, with disruption selectively impairing social recognition and working memory.","evidence":"Stereotaxic AAV manipulation in mouse mPFC with construct controls and behavioral battery","pmids":["36513018"],"confidence":"Medium","gaps":["Single lab","Downstream signaling in mPFC not dissected"]},{"year":null,"claim":"The high-resolution structural basis of the heterodivalent ExF/PDZ nNOS engagement and the identity of the additional structured element remain unresolved, as does whether the disease-relevant partners (tau, α-synuclein, MKK3) bind through shared or distinct surfaces.","evidence":"No structural or domain-resolution study in the corpus addresses these questions","pmids":[],"confidence":"Low","gaps":["No crystal/cryo-EM structure of NOS1AP–nNOS","Binding domains for tau and α-synuclein unmapped","Whether neuronal and cardiac functions share regulatory mechanisms unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,2,5,7,11]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,3,11,23,27]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[10]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[29]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[19]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[9,28,30]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[29]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,7,10]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,2,4,8]},{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[3,23,27,31]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[7,16,22]}],"complexes":["nNOS–CAPON–Dexras1 ternary complex","nNOS–CAPON–synapsin I complex","Scribble–β-Pix/Git1/PAK complex","SCRIB–VANGL1–NOS1AP complex"],"partners":["NOS1","DEXRAS1","SYN1","SCRIB","CPE","MAP2K3","YAP1","MAPT"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75052","full_name":"Carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase protein","aliases":["C-terminal PDZ ligand of neuronal nitric oxide synthase protein","Nitric oxide synthase 1 adaptor protein"],"length_aa":506,"mass_kda":56.1,"function":"Adapter protein involved in neuronal nitric-oxide (NO) synthesis regulation via its association with nNOS/NOS1. The complex formed with NOS1 and synapsins is necessary for specific NO and synapsin functions at a presynaptic level. Mediates an indirect interaction between NOS1 and RASD1 leading to enhance the ability of NOS1 to activate RASD1. Competes with DLG4 for interaction with NOS1, possibly affecting NOS1 activity by regulating the interaction between NOS1 and DLG4 (By similarity). In kidney podocytes, plays a role in podosomes and filopodia formation through CDC42 activation (PubMed:33523862)","subcellular_location":"Cell projection, filopodium; Cell projection, podosome","url":"https://www.uniprot.org/uniprotkb/O75052/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NOS1AP","classification":"Not Classified","n_dependent_lines":93,"n_total_lines":1208,"dependency_fraction":0.07698675496688742},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NOS1AP","total_profiled":1310},"omim":[{"mim_id":"619155","title":"NEPHROTIC SYNDROME, TYPE 22; NPHS22","url":"https://www.omim.org/entry/619155"},{"mim_id":"610141","title":"QT INTERVAL, VARIATION IN","url":"https://www.omim.org/entry/610141"},{"mim_id":"605551","title":"NITRIC OXIDE SYNTHASE 1 (NEURONAL) ADAPTOR PROTEIN; NOS1AP","url":"https://www.omim.org/entry/605551"},{"mim_id":"605550","title":"RAS PROTEIN, DEXAMETHASONE-INDUCED, 1; RASD1","url":"https://www.omim.org/entry/605550"},{"mim_id":"256300","title":"NEPHROTIC SYNDROME, TYPE 1; NPHS1","url":"https://www.omim.org/entry/256300"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":16.3}],"url":"https://www.proteinatlas.org/search/NOS1AP"},"hgnc":{"alias_symbol":["KIAA0464","CAPON"],"prev_symbol":[]},"alphafold":{"accession":"O75052","domains":[{"cath_id":"2.30.29.30","chopping":"22-88_103-175","consensus_level":"medium","plddt":92.9239,"start":22,"end":175}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75052","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75052-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75052-F1-predicted_aligned_error_v6.png","plddt_mean":64.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NOS1AP","jax_strain_url":"https://www.jax.org/strain/search?query=NOS1AP"},"sequence":{"accession":"O75052","fasta_url":"https://rest.uniprot.org/uniprotkb/O75052.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75052/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75052"}},"corpus_meta":[{"pmid":"9459447","id":"PMC_9459447","title":"CAPON: 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CAPON competes with PSD95 for interaction with nNOS, and overexpression of CAPON results in loss of PSD95/nNOS complexes in transfected cells.\",\n      \"method\": \"Co-immunoprecipitation, transfection/overexpression in cells, competition binding assay\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with functional overexpression readout, foundational paper replicated by many subsequent studies\",\n      \"pmids\": [\"9459447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CAPON (NOS1AP) selectively interacts with Dexras1, a brain-enriched Ras-family small G protein, forming a ternary complex with nNOS and CAPON that enhances NO-mediated activation of Dexras1. NMDA receptor-stimulated NO synthesis activates Dexras1 in cortical neurons, and this activation is selectively reduced in nNOS-knockout mice.\",\n      \"method\": \"Co-immunoprecipitation, ternary complex reconstitution, cortical neuron experiments, nNOS-knockout mouse model\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genetic knockout model, multiple orthogonal methods in one study\",\n      \"pmids\": [\"11086993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CAPON (NOS1AP) interacts with synapsins I, II, and III through an N-terminal phosphotyrosine-binding (PTB) domain interaction, forming a ternary complex comprising nNOS, CAPON, and synapsin I. Loss of synapsin I and II in double-knockout mice alters the subcellular localization of nNOS, demonstrating the functional importance of this complex for nNOS targeting to presynaptic sites.\",\n      \"method\": \"Co-immunoprecipitation, PTB domain binding assay, synapsin I/II double-knockout mouse localization studies\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with domain mapping plus genetic epistasis in knockout mice showing localization consequence\",\n      \"pmids\": [\"11867766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CAPON (NOS1AP) protein is expressed in the heart, interacts with NOS1, and accelerates cardiac repolarization by inhibition of the L-type calcium channel in ventricular myocytes.\",\n      \"method\": \"Protein expression analysis (Western blot), co-immunoprecipitation, electrophysiology in isolated ventricular myocytes with CAPON overexpression\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for interaction, direct electrophysiology with overexpression showing L-type Ca channel inhibition, multiple orthogonal methods in one study\",\n      \"pmids\": [\"18337493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"NOS1AP (long isoform, NOS1AP-L) regulates dendrite outgrowth and branching in cultured hippocampal neurons. The middle region (amino acids 181–307), not the PDZ-binding or PTB domains, mediates this effect, and carboxypeptidase E (CPE) was identified as a binding partner for this middle region that mediates NOS1AP's effects on dendrite morphology.\",\n      \"method\": \"Overexpression/knockdown in cultured hippocampal neurons, NOS1AP deletion mutants, yeast two-hybrid screen, biochemical and cellular validation of CPE interaction\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping with multiple deletion mutants, yeast two-hybrid plus cellular validation of CPE as binding partner, functional rescue experiments\",\n      \"pmids\": [\"19553464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"NOS1AP associates directly with Scribble through the NOS1AP PTB domain and the fourth PDZ domain of Scribble. Scribble bridges NOS1AP to a β-Pix/Git1/PAK complex. Overexpression of NOS1AP increases dendritic protrusions in a PTB domain-dependent manner, and both full-length NOS1AP and the PTB domain influence Rac activity.\",\n      \"method\": \"Proteomic screen, direct binding assay, co-immunoprecipitation, overexpression in neurons, Rac activity assay\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding established by multiple methods, domain mapping, functional Rac activity assay with overexpression phenotype\",\n      \"pmids\": [\"20357130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NOS1AP forms a protein complex with SCRIB and VANGL1 along cellular protrusions in metastatic breast cancer cells. shRNA-mediated knockdown of NOS1AP slows breast cancer cell migration and prevents establishment of leading-trailing polarity; reduction of NOS1AP also enhances anchorage-independent growth.\",\n      \"method\": \"Mass spectrometry, confocal microscopy, shRNA knockdown, cell migration assay, anchorage-independent growth assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry identification of complex, shRNA knockdown with specific cellular phenotypes, single lab\",\n      \"pmids\": [\"22179838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NOS1AP interacts with p38MAPK-activating kinase MKK3. Excitotoxic stimulation induces recruitment of NOS1AP to nNOS in rat cortical neurons. Excitotoxic activation of p38MAPK and subsequent neuronal death are reduced by competing with the nNOS:NOS1AP interaction or by NOS1AP siRNA knockdown. A cell-permeable peptide competing for nNOS:NOS1AP interaction doubles surviving tissue in a rat neonatal hypoxia-ischemia model.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, cell-permeable competing peptide, in vivo rat hypoxia-ischemia model\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP of MKK3 interaction, siRNA knockdown with specific readout, in vivo validation with competing peptide, multiple orthogonal methods\",\n      \"pmids\": [\"23658158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Augmenting nNOS-CAPON interaction in mouse hippocampus by CAPON overexpression produces anxiogenic behaviors, while dissociating CAPON from nNOS by overexpressing truncated CAPON fragments or delivering Tat-CAPON-12C peptide produces anxiolytic effects. The mechanism involves Dexras1-ERK signaling downstream of nNOS-CAPON association.\",\n      \"method\": \"Viral overexpression in mouse hippocampus, behavioral assays (anxiety), chronic mild stress model, Dexras1-ERK signaling pathway analysis\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic and pharmacological manipulations of the nNOS-CAPON interaction with specific behavioral readouts, pathway identification via Dexras1-ERK\",\n      \"pmids\": [\"25129479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A noncoding polymorphism (rs7539120) within an enhancer of NOS1AP affects cardiac function by increasing NOS1AP transcript expression. NOS1AP localizes to cardiomyocyte intercalated discs, and overexpression of NOS1AP in cardiomyocytes alters cellular electrophysiology.\",\n      \"method\": \"Enhancer reporter assays, human genetic and molecular genetic assays, NOS1AP localization by cellular fractionation/immunostaining, cardiomyocyte electrophysiology with overexpression\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple human genetic, molecular genetic, and cellular assays identifying functional variant, localization experiment with functional electrophysiology consequence\",\n      \"pmids\": [\"24857694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NOS1AP functionally associates with the transcriptional coactivator YAP. Silencing NOS1AP reduces phosphorylation of YAP and of the upstream kinase Lats1; conversely, NOS1AP expression promotes YAP and Lats1 phosphorylation, correlating with reduced TEAD activity and restricted cell proliferation. NOS1AP isoforms with a membrane-interacting PTB domain associate with Scribble and recognize acidic phospholipids.\",\n      \"method\": \"Co-immunoprecipitation (NOS1AP-YAP complex), siRNA silencing with YAP/Lats1 phosphorylation readout, TEAD reporter assay, cell proliferation assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of YAP complex, gain- and loss-of-function with pathway readouts, single lab\",\n      \"pmids\": [\"25918243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The interaction of NOS1AP with nNOS is not mediated solely by the classical C-terminal PDZ motif as previously assumed. The PDZ motif of NOS1AP is neither sufficient nor necessary for binding nNOS as measured by multiple methods; instead, a novel internal ExF motif is required for interaction. Full-length NOS1AP forms an unusually stable heterodivalent interaction with nNOS through both the ExF motif and the PDZ ligand motif.\",\n      \"method\": \"Multiple binding assays (in vitro and cellular), domain mapping, mutagenesis of PDZ and ExF motifs, cortical neuron excitotoxicity assays\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple binding assays with mutagenesis of key motifs, functional validation in neurons, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"25972165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NOS1AP overexpression in hippocampal and cortical neurons causes highly altered spine morphology and excessive growth of filopodia-like protrusions. Interaction with the NOS-I PDZ domain (confirmed by co-immunoprecipitation) contributes to these effects on dendritic spine plasticity.\",\n      \"method\": \"Co-immunoprecipitation, overexpression of NOS1AP isoforms and deletion mutants in primary cultured neurons, Sholl analysis, spine morphology quantification\",\n      \"journal\": \"European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus overexpression with morphological phenotype, domain mapping, single lab\",\n      \"pmids\": [\"26861996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The concerted action of the ExF motif and PDZ ligand motif of NOS1AP efficiently excludes an alternate ligand from the nNOS PDZ ligand-binding pocket. An additional structured element (denaturable) contributes to the interaction; its denaturation selectively prevents the concerted action of the two motifs, resulting in ~30-fold reduction in competition with alternate PDZ ligands despite only ~3-fold drop in overall binding affinity.\",\n      \"method\": \"In vitro binding competition assays, mutagenesis of ExF and PDZ motifs, denaturation experiments with binding affinity measurements\",\n      \"journal\": \"Frontiers in molecular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro biochemical assays with mutagenesis, single lab, single study\",\n      \"pmids\": [\"28360833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TAT-GESV, a peptide inhibitor of the nNOS-NOS1AP complex, disrupts in vitro binding between nNOS and NOS1AP but not between nNOS and its upstream partner PSD95. Disruption of nNOS-NOS1AP interaction suppresses mechanical and cold allodynia in paclitaxel-induced and nerve ligation neuropathic pain models, and blocks paclitaxel-induced phosphorylation of p53 at Ser15 (a p38 MAPK substrate).\",\n      \"method\": \"In vitro binding assay, cortical neuron excitotoxicity assay, intrathecal peptide administration in rodent pain models, p38 MAPK substrate phosphorylation measurement\",\n      \"journal\": \"Pain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding assay, in vivo pain model with specific signaling readout, but peptide specificity relies on prior characterization\",\n      \"pmids\": [\"29319606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Increased nNOS-CAPON interaction was detected after amyloid-β treatment in cultured neurons and in the hippocampus of APP/PS1 transgenic mice. Blocking nNOS-CAPON interaction rescued memory in 4-month-old APP/PS1 mice and ameliorated dendritic impairments. S-nitrosylation of Dexras1 and inhibition of the ERK-CREB-BDNF pathway were identified as downstream consequences of nNOS-CAPON interaction.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay, APP/PS1 mouse model, behavioral memory testing, dendritic spine analysis, Dexras1 S-nitrosylation measurement, ERK-CREB-BDNF pathway Western blot\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vitro and in vivo methods, pathway characterization, single lab\",\n      \"pmids\": [\"29577585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CAPON (NOS1AP) was identified as a novel tau-binding protein by immunoprecipitation/LC-MS screening. CAPON overexpression in AppNL-G-F/human-tau knock-in mice produced significant hippocampal atrophy, caspase3-dependent neuronal death, and higher levels of phosphorylated, oligomerized, and insoluble tau. CAPON deficiency ameliorated AD-related pathological phenotypes in a tauopathy model.\",\n      \"method\": \"Immunoprecipitation/LC-MS (tau interactome screen), AAV overexpression in transgenic mice, histopathology, tau biochemical fractionation, CAPON knockout in tauopathy model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — unbiased IP/MS identification validated by both gain-of-function and loss-of-function in vivo models with multiple readouts\",\n      \"pmids\": [\"31160584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Stroke increases nNOS-CAPON association in the peri-infarct cortex during the delayed period. Inhibiting the ischemia-induced nNOS-CAPON association promotes functional recovery (reduced foot faults, forelimb asymmetry), facilitates dendritic remodeling (increased spine density, branching), and enhances synaptic transmission (increased mEPSC frequency), but does not affect neuronal loss or infarct size.\",\n      \"method\": \"Co-immunoprecipitation, AAV-mediated NOS1AP fragment overexpression, Tat-CAPON-12C and ZLc-002 peptide/small molecule in photothrombotic stroke and tMCAO mouse models, behavioral assessment, Golgi staining, electrophysiology\",\n      \"journal\": \"Stroke\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple pharmacological and genetic tools targeting nNOS-CAPON interaction, two stroke models, multiple orthogonal cellular and behavioral readouts\",\n      \"pmids\": [\"30727847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CAPON-immunoreactivity is increased in the DLPFC and anterior cingulate cortex in MDD patients, accompanied by upregulation of spinophilin and downregulation of synapsin. CAPON colocalizes with spinophilin in the DLPFC of MDD patients and interacts with spinophilin in human brain. Viral-mediated CAPON downregulation in mouse medial PFC reverses depression-like behaviors in CUMS mice.\",\n      \"method\": \"Immunohistochemistry in postmortem brain, co-immunoprecipitation (CAPON-spinophilin interaction in human brain), AAV-mediated knockdown in mouse PFC with behavioral assays\",\n      \"journal\": \"Cerebral cortex (New York, N.Y. : 1991)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP in human brain tissue, in vivo loss-of-function with behavioral readout, single lab but human plus mouse validation\",\n      \"pmids\": [\"30307500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CAPON (NOS1AP) localizes with NOS1 in cardiac sarcoplasmic reticulum (SR) fractions; co-immunoprecipitation confirmed CAPON interaction with mu and alpha isoforms of NOS1 in whole heart lysates. Following myocardial infarction, CAPON and NOS1 redistribute to caveolae and colocalize with caveolin-3. In NOS1-deficient cardiomyocytes, CAPON abundance in the SR is reduced. CAPON also associates with xanthine oxidoreductase and plasma membrane calcium ATPase (PMCA) in infarcted hearts.\",\n      \"method\": \"Subcellular fractionation, co-immunoprecipitation, dual immuno-gold electron microscopy, NOS1-knockout mice\",\n      \"journal\": \"Nitric oxide : biology and chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — subcellular fractionation plus immuno-gold EM for localization, Co-IP for interactions, NOS1 knockout for functional dependence, multiple orthogonal methods\",\n      \"pmids\": [\"19800018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In chronic heart failure (CHF), CAPON expression is augmented in the paraventricular nucleus (PVN), concomitant with decreased nNOS, disconnecting the NR1-nNOS link and contributing to enhanced sympathoexcitation. Angiotensin II type 1 receptor (AT1) antagonist losartan treatment normalizes CAPON and nNOS expression and reduces renal sympathetic nerve activity. Ang II directly increases CAPON expression in NG108 neuronal cells, reversed by AT1 blockade.\",\n      \"method\": \"Western blot in PVN of CHF rats, renal sympathetic nerve activity recording, losartan pharmacological intervention, Ang II treatment in neuronal cell culture\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo model with pharmacological rescue, in vitro Ang II experiment, single lab, mechanism inferred from expression changes\",\n      \"pmids\": [\"21831995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CAPON expression is significantly reduced in stellate ganglia of spontaneously hypertensive rats before development of hypertension. Targeted upregulation of CAPON using a noradrenergic-specific viral vector significantly upregulated NOS1 activity and cGMP, reduced neuronal calcium current (ICa) and intracellular calcium transients, and reduced norepinephrine release from atria. These effects were reversed by NOS1 inhibition.\",\n      \"method\": \"Viral vector (Ad.PRSx8-mCherry/CAPON) overexpression in stellate ganglia neurons, patch-clamp electrophysiology, calcium imaging, NOS1 activity assay, cGMP measurement, 3H-norepinephrine release assay\",\n      \"journal\": \"Hypertension (Dallas, Tex. : 1979)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct overexpression with multiple cellular physiological readouts plus pharmacological NOS1 inhibition as confirmatory reversal, multiple orthogonal methods\",\n      \"pmids\": [\"25916729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"O-GlcNAc modification occurs on NOS1AP at Ser47, Ser183, Ser204, Ser269, and Ser271 (identified by mass spectrometry). O-GlcNAc modification levels of NOS1AP increase during glutamate-induced neuronal apoptosis. Mutation of O-GlcNAc sites decreases the interaction of NOS1AP with nNOS. Decreasing NOS1AP O-GlcNAc modification results in more severe neuronal apoptosis.\",\n      \"method\": \"Mass spectrometry (O-GlcNAc site identification), site-directed mutagenesis, co-immunoprecipitation, neuronal apoptosis assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mass spec site identification, mutagenesis with functional Co-IP readout, single lab\",\n      \"pmids\": [\"26197318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NOS1AP minor alleles (rs16847548 and rs4657139) are associated with reduced NOS1 expression, reduced NOS1AP-NOS1 co-localization in hiPSC-CMs from symptomatic LQT1 patients, and functional NOS1 loss of function (prolonged APD, enhanced ICaL, and perturbed calcium handling). In guinea pig cardiomyocytes, NOS1 inhibition prolonged APD, enhanced ICaL and INaL, slowed Ca2+ decay, and induced delayed afterdepolarizations, establishing a mechanistic link between NOS1AP variants and arrhythmia phenotype.\",\n      \"method\": \"hiPSC-CMs from LQT1 patients with different NOS1AP genotypes, guinea pig cardiomyocyte pharmacological NOS1 inhibition, patch-clamp electrophysiology, calcium imaging, action potential clamp\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — electrophysiology in patient-derived iPSC-CMs plus pharmacological model, multiple cellular readouts, mechanistic pathway established\",\n      \"pmids\": [\"32061134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Hippocampal overexpression of NOS1AP markedly increased the interaction of nNOS with PSD-95, reduced dendritic spine density, and changed dendritic spine morphology at CA1 synapses. This produced behavioral impairment in social memory and spatial working memory.\",\n      \"method\": \"AAV overexpression in mouse hippocampus, co-immunoprecipitation (nNOS-PSD-95 interaction), Golgi staining and spine morphology analysis, behavioral testing\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — viral overexpression with Co-IP and morphological plus behavioral readouts, single lab\",\n      \"pmids\": [\"34455393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NOS1AP mRNA is a direct TDP-43 target (identified by transcriptome analysis). TDP-43-mediated downregulation of NOS1AP expression strongly affects NMDA-receptor signaling in primary mouse cortical neurons. In Drosophila, modulation of NOS1AP alone can rescue TDP-43 pathology.\",\n      \"method\": \"Transcriptome analysis, Drosophila genetic rescue experiments, primary mouse cortical neuron NMDA-receptor signaling assays\",\n      \"journal\": \"Brain communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptomics plus genetic epistasis in Drosophila and neuronal signaling assay, single lab\",\n      \"pmids\": [\"36267332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NOS1AP interacts with α-synuclein and forms detergent-resistant non-amyloid aggregates when overproduced. This interaction was demonstrated in yeast and mammalian cells, suggesting NOS1AP may be implicated in synucleinopathies.\",\n      \"method\": \"Bioinformatics aggregation prediction, overexpression in yeast and mammalian cells (detergent-resistant aggregate detection), co-aggregation assay with α-synuclein\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, aggregation shown by overexpression without mutagenesis or in vivo validation, interaction with α-synuclein not rigorously demonstrated by direct binding assay\",\n      \"pmids\": [\"36012368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cardiac-specific overexpression of Nos1ap in transgenic mice leads to increased L-type calcium channel nitrosylation (S-nitrosylation via NOS1), shortening of APD90, decreased QT interval duration, increased susceptibility to ventricular tachycardias, and reduced survival. Overexpression did not alter cGMP or ROS levels.\",\n      \"method\": \"Conditional transgenic mouse model with cardiac-specific Nos1ap overexpression, whole-cell patch-clamp, optical mapping, ECG/telemetry, immunochemistry for nitrosylation\",\n      \"journal\": \"FEBS open bio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic model with electrophysiology and mechanistic L-type Ca channel nitrosylation readout, single lab\",\n      \"pmids\": [\"36352324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NOS1AP enhancer polymorphism rs7539120 increases NOS1AP transcript expression, and NOS1AP localizes to cardiomyocyte intercalated discs. Overexpression in cardiomyocytes leads to altered cellular electrophysiology, supporting a role for NOS1AP in cardiac electrical conductance and QT interval regulation through propagation defects.\",\n      \"method\": \"Enhancer reporter assay, immunostaining for intercalated disc localization, cardiomyocyte electrophysiology with NOS1AP overexpression\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays (enhancer reporter, localization, electrophysiology) in one study, single lab\",\n      \"pmids\": [\"24857694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CAPON (NOS1AP) undergoes nuclear translocation in astrocytes stimulated with NO donors (SNP, GSNO) or NMDA receptor agonist; it localizes predominantly in the cytoplasm under basal conditions. nNOS co-localizes with CAPON in the nucleus of stimulated astrocytes. NMDA receptor antagonist MK801 reverses the nuclear localization of CAPON induced by SNP.\",\n      \"method\": \"Immunocytochemistry, real-time PCR, Western blot, pharmacological manipulation (NO donors, MK801)\",\n      \"journal\": \"Neurochemistry international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, localization by immunostaining with pharmacological manipulation, no direct functional consequence of nuclear localization established\",\n      \"pmids\": [\"20064573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NOS1AP silencing in cardiac myocytes reduces electrically evoked calcium transient amplitude and degree of S-nitrosylation. NOS1AP shows high co-localization with the L-type calcium channel and inwardly rectifying potassium channel Kir3.1, low co-localization with RyR2, and no co-localization with connexin 43. NOS1AP is upregulated in dystrophic cardiomyopathy mice.\",\n      \"method\": \"siRNA knockdown, calcium imaging, S-nitrosylation assay, confocal co-localization microscopy, immunofluorescence/Western blot in dystrophic cardiomyopathy model\",\n      \"journal\": \"International journal of physiology, pathophysiology and pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with calcium and nitrosylation readouts, co-localization with ion channels, single lab\",\n      \"pmids\": [\"24665357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Nos1ap knockout mice develop normally but are highly susceptible to oxidative stress (doxorubicin)-induced ventricular tachyarrhythmias, QTc prolongation, impaired cardiac function (reduced fractional shortening), and increased mortality. Ex vivo optical mapping showed APD90 is prolonged at baseline and further lengthened by doxorubicin in Nos1ap-/- mice. Calcium transient amplitude is reduced in Nos1ap-/- cardiomyocytes after doxorubicin, and antioxidant N-acetyl-L-cysteine rescued these phenotypes.\",\n      \"method\": \"Nos1ap knockout mouse model, ECG/telemetry, echocardiography, ex vivo optical mapping, calcium imaging in isolated cardiomyocytes, pharmacological rescue with antioxidant\",\n      \"journal\": \"International heart journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mouse model with multiple cardiac physiology readouts and pharmacological rescue, single lab\",\n      \"pmids\": [\"27170476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Disruption of NOS1AP/nNOS interaction in the medial prefrontal cortex (by AAV overexpression of NOS1AP, NOS1AP396-503, or nNOS1-133) impairs social recognition and spatial working memory capacity in mice, without affecting anxiety, social interaction, or spatial reference memory.\",\n      \"method\": \"Stereotaxic AAV injection in mouse mPFC, comprehensive behavioral battery, genetic dissection of nNOS/NOS1AP/PSD-95 interactions\",\n      \"journal\": \"European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — region-specific viral manipulation with multiple construct controls and specific behavioral readouts, single lab\",\n      \"pmids\": [\"36513018\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NOS1AP (CAPON) is a multifunctional adaptor protein that binds the PDZ domain of neuronal nitric oxide synthase (nNOS) via a heterodivalent mechanism involving both a C-terminal PDZ motif and an internal ExF motif, competitively displacing PSD95 from nNOS and thereby modulating NMDA receptor-coupled NO signaling; through its N-terminal PTB domain it also scaffolds nNOS to synapsins (targeting nNOS to presynaptic sites), Dexras1 (forming a ternary nNOS–CAPON–Dexras1 complex that enhances NO-mediated Dexras1/ERK signaling), Scribble (linking to β-Pix/Git1/PAK and Hippo/YAP pathways), carboxypeptidase E (regulating dendrite morphology), and spinophilin (in the prefrontal cortex); in the heart, CAPON co-localizes with NOS1 at the sarcoplasmic reticulum and intercalated discs, inhibits L-type calcium channels via NOS1-dependent S-nitrosylation to accelerate repolarization, and loss of NOS1AP sensitizes cardiomyocytes to arrhythmia under oxidative stress; NOS1AP also interacts with MKK3 to mediate excitotoxic p38MAPK activation and neuronal death, undergoes protective O-GlcNAc modification that stabilizes nNOS binding, and is subject to nuclear translocation in inflammatory contexts, while its overall level of interaction with nNOS is regulated by the 5-HT1A receptor, Angiotensin II/AT1 signaling, and chronic stress.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NOS1AP (CAPON) is a cytoplasmic adaptor protein that organizes neuronal nitric oxide synthase (nNOS/NOS1) signaling by competing with PSD95 for the nNOS PDZ domain and thereby tuning NMDA receptor-coupled NO output [#0]. The nNOS interaction is not a simple PDZ-motif contact: full-length NOS1AP forms an unusually stable heterodivalent interaction through both an internal ExF motif and the C-terminal PDZ ligand motif, whose concerted action efficiently excludes competing PDZ ligands from the nNOS binding pocket [#11, #13]. Through its N-terminal PTB domain, NOS1AP scaffolds nNOS to additional partners that nucleate distinct downstream pathways: Dexras1, forming a ternary nNOS–CAPON–Dexras1 complex that enhances NO-mediated Dexras1 activation and ERK signaling [#1, #8]; synapsins, which target nNOS to presynaptic sites [#2]; Scribble, which bridges NOS1AP to a β-Pix/Git1/PAK module and regulates Rac activity, dendritic protrusions, and the Lats1/YAP/TEAD axis [#5, #10]; and MKK3, linking excitotoxic stimulation to p38MAPK activation and neuronal death [#7]. NOS1AP regulates dendrite outgrowth and spine morphology, with a central region (aa 181–307) binding carboxypeptidase E to control dendrite branching [#4, #12]. Acute augmentation of the nNOS–CAPON interaction is pathogenic across neurological contexts—anxiety, ischemic stroke, amyloid-β toxicity, and neuropathic pain—and peptide disruptors of the complex are neuroprotective and behaviorally corrective [#8, #14, #15, #17]. In the heart, NOS1AP co-localizes with NOS1 at the sarcoplasmic reticulum and intercalated discs, and through NOS1-dependent S-nitrosylation inhibits the L-type calcium channel to accelerate repolarization and shorten action potential duration; both overexpression and loss of NOS1AP are arrhythmogenic, the latter sensitizing cardiomyocytes to oxidative-stress-induced ventricular tachyarrhythmia [#3, #19, #23, #27, #31]. NOS1AP has been identified as a tau- and α-synuclein-interacting protein whose levels modulate tauopathy and synucleinopathy phenotypes [#16, #26].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established NOS1AP's founding identity by showing it binds the nNOS PDZ domain and can displace PSD95, defining it as a competitive regulator of nNOS scaffolding.\",\n      \"evidence\": \"Co-immunoprecipitation and competition binding with overexpression in transfected cells\",\n      \"pmids\": [\"9459447\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the binding determinants beyond the C-terminal motif\", \"Functional consequence on NO output in neurons not addressed\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defined a downstream effector pathway by showing CAPON forms a ternary complex with nNOS and Dexras1, coupling NMDA-stimulated NO synthesis to small G-protein activation.\",\n      \"evidence\": \"Reciprocal Co-IP, ternary complex reconstitution, cortical neurons, nNOS-knockout mice\",\n      \"pmids\": [\"11086993\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map which CAPON domain binds Dexras1\", \"Physiological readout of Dexras1 activation in vivo not established\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identified the PTB domain as a presynaptic targeting module by showing CAPON bridges nNOS to synapsins, with knockout altering nNOS localization.\",\n      \"evidence\": \"Co-IP with PTB domain mapping plus synapsin I/II double-knockout localization studies\",\n      \"pmids\": [\"11867766\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional impact on presynaptic NO signaling not measured\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extended NOS1AP function to the heart by demonstrating it interacts with NOS1 and accelerates cardiac repolarization via L-type calcium channel inhibition.\",\n      \"evidence\": \"Co-IP and electrophysiology in isolated ventricular myocytes with CAPON overexpression\",\n      \"pmids\": [\"18337493\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of channel inhibition (S-nitrosylation) not yet shown\", \"Endogenous loss-of-function consequence not tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolved cardiac subcellular organization, showing CAPON localizes with NOS1 at the sarcoplasmic reticulum and redistributes to caveolae after infarction, with NOS1 controlling CAPON abundance.\",\n      \"evidence\": \"Subcellular fractionation, Co-IP, dual immuno-gold EM, NOS1-knockout mice\",\n      \"pmids\": [\"19800018\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of caveolar redistribution not established\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined a non-canonical dendritic morphogenesis role by mapping dendrite branching to a central region binding carboxypeptidase E, distinct from the nNOS-binding domains.\",\n      \"evidence\": \"Deletion mutants, yeast two-hybrid, and cellular validation in cultured hippocampal neurons\",\n      \"pmids\": [\"19553464\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking CPE binding to cytoskeletal remodeling unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected NOS1AP to actin/polarity signaling by showing direct PTB-domain binding to Scribble, bridging to a β-Pix/Git1/PAK complex and regulating Rac and dendritic protrusions.\",\n      \"evidence\": \"Proteomic screen, direct binding assay, Co-IP, Rac activity assay in neurons\",\n      \"pmids\": [\"20357130\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether nNOS participates in this complex not addressed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Reported stimulus-dependent nuclear translocation of CAPON in astrocytes upon NO/NMDA stimulation, raising a possible nuclear function.\",\n      \"evidence\": \"Immunocytochemistry and Western blot with NO donors and MK801 in astrocytes\",\n      \"pmids\": [\"20064573\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No functional consequence of nuclear localization established\", \"Single lab, immunostaining-based observation\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended Scribble-pathway involvement to cancer cell migration by placing NOS1AP in a SCRIB/VANGL1 complex required for polarity and motility.\",\n      \"evidence\": \"Mass spectrometry, confocal microscopy, shRNA knockdown with migration and growth assays in breast cancer cells\",\n      \"pmids\": [\"22179838\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct binding to VANGL1 vs indirect via Scribble not dissected\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linked CAPON to autonomic cardiovascular control by showing it is upregulated in the paraventricular nucleus during heart failure under Angiotensin II/AT1 signaling, contributing to sympathoexcitation.\",\n      \"evidence\": \"Western blot in CHF rat PVN, renal sympathetic nerve recording, losartan rescue, Ang II treatment in neuronal cells\",\n      \"pmids\": [\"21831995\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism inferred from expression changes\", \"Direct causal manipulation of CAPON in PVN not performed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified an excitotoxic death pathway by showing NOS1AP recruits MKK3 to nNOS to activate p38MAPK, with peptide disruption protective in hypoxia-ischemia.\",\n      \"evidence\": \"Co-IP, siRNA knockdown, cell-permeable competing peptide, rat neonatal hypoxia-ischemia model\",\n      \"pmids\": [\"23658158\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MKK3 binds the same domain as other partners not mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated behavioral significance of the nNOS–CAPON interaction in anxiety, with bidirectional manipulation acting through Dexras1-ERK signaling.\",\n      \"evidence\": \"Viral overexpression and Tat-peptide disruption in mouse hippocampus, chronic mild stress, pathway analysis\",\n      \"pmids\": [\"25129479\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Circuit-level locus of action beyond hippocampus not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Provided a human-genetic mechanistic link by showing an enhancer polymorphism increases NOS1AP expression and that NOS1AP at intercalated discs alters cardiomyocyte electrophysiology.\",\n      \"evidence\": \"Enhancer reporter assays, human genetics, localization by immunostaining, cardiomyocyte electrophysiology\",\n      \"pmids\": [\"24857694\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise conduction mechanism at intercalated discs unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Overturned the simple PDZ-motif model by demonstrating that an internal ExF motif, not the C-terminal PDZ ligand alone, is required for nNOS binding, with full-length NOS1AP forming a stable heterodivalent interaction.\",\n      \"evidence\": \"Multiple in vitro and cellular binding assays with mutagenesis of PDZ and ExF motifs, neuronal excitotoxicity assays\",\n      \"pmids\": [\"25972165\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of dual-motif engagement not solved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected NOS1AP to Hippo signaling by showing it promotes Lats1 and YAP phosphorylation, restraining TEAD activity and proliferation, with PTB-domain phospholipid recognition.\",\n      \"evidence\": \"Co-IP, siRNA, TEAD reporter and proliferation assays\",\n      \"pmids\": [\"25918243\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct vs Scribble-mediated effect on Lats1 not separated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified a sympathetic-neuron protective role, where CAPON upregulation enhances NOS1 activity and cGMP to reduce calcium currents and norepinephrine release, deficient in pre-hypertensive rats.\",\n      \"evidence\": \"Noradrenergic-specific viral overexpression in stellate ganglia, patch-clamp, calcium imaging, NOS1 activity and norepinephrine release assays\",\n      \"pmids\": [\"25916729\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CAPON loss drives hypertension causally not proven\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Described a regulatory PTM by mapping O-GlcNAc sites on NOS1AP that stabilize nNOS binding and are protective against glutamate-induced apoptosis.\",\n      \"evidence\": \"Mass spectrometry site identification, mutagenesis, Co-IP, neuronal apoptosis assay\",\n      \"pmids\": [\"26197318\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Enzyme responsible for site-specific modification not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined cardiac calcium-handling function by showing NOS1AP silencing reduces calcium transients and S-nitrosylation, with selective co-localization to L-type calcium and Kir3.1 channels.\",\n      \"evidence\": \"siRNA knockdown, calcium imaging, S-nitrosylation assay, confocal co-localization in cardiac myocytes\",\n      \"pmids\": [\"24665357\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Causal nitrosylation targets beyond L-type channel not fully mapped\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed dose-sensitivity of NOS1AP in dendritic spine plasticity, where overexpression produces aberrant filopodia-like protrusions dependent on nNOS PDZ interaction.\",\n      \"evidence\": \"Co-IP, overexpression of isoforms and deletion mutants, Sholl and spine analysis in primary neurons\",\n      \"pmids\": [\"26861996\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Endogenous role at physiological levels not isolated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established loss-of-function cardiac vulnerability, showing Nos1ap-null mice are normal at baseline but highly arrhythmia-prone under oxidative stress, rescued by antioxidant.\",\n      \"evidence\": \"Nos1ap knockout mice, ECG/telemetry, echocardiography, optical mapping, calcium imaging, N-acetyl-cysteine rescue\",\n      \"pmids\": [\"27170476\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Molecular link between NOS1AP loss and oxidative sensitivity not fully resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Refined the binding mechanism by showing the ExF and PDZ motifs act concertedly to exclude competing ligands, with an additional structured element required for efficient competition.\",\n      \"evidence\": \"In vitro binding competition assays, mutagenesis, denaturation experiments with affinity measurement\",\n      \"pmids\": [\"28360833\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the structured element not determined\", \"No high-resolution structure\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated therapeutic disruption of nNOS-NOS1AP in neuropathic pain, with the TAT-GESV peptide reducing allodynia and p38-dependent p53 phosphorylation while sparing nNOS-PSD95.\",\n      \"evidence\": \"In vitro binding assay, rodent paclitaxel and nerve-ligation pain models, signaling readout\",\n      \"pmids\": [\"29319606\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Peptide specificity relies on prior characterization\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Implicated NOS1AP in amyloid pathology by showing amyloid-β increases nNOS-CAPON interaction, with disruption rescuing memory via Dexras1 S-nitrosylation and ERK-CREB-BDNF signaling.\",\n      \"evidence\": \"Co-IP, proximity ligation assay, APP/PS1 mice, behavioral and dendritic readouts, pathway Western blots\",\n      \"pmids\": [\"29577585\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Causal sequence linking interaction to BDNF suppression not fully dissected\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified CAPON as a tau-binding protein whose dosage bidirectionally controls tauopathy, with overexpression driving neuronal death and deficiency ameliorating pathology.\",\n      \"evidence\": \"IP/LC-MS tau interactome, AAV overexpression and knockout in tauopathy mice, histopathology and tau biochemistry\",\n      \"pmids\": [\"31160584\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether tau binding depends on nNOS interaction not determined\", \"Binding domain on CAPON not mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated that nNOS-CAPON disruption promotes post-stroke recovery and dendritic/synaptic remodeling without altering infarct size, separating repair from initial injury.\",\n      \"evidence\": \"Co-IP, AAV and peptide/small-molecule disruption in two stroke models, behavior, Golgi staining, electrophysiology\",\n      \"pmids\": [\"30727847\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of dendritic remodeling downstream of disruption not detailed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked CAPON to depression by showing it is elevated in patient prefrontal cortex, interacts with spinophilin, and its knockdown reverses depression-like behavior.\",\n      \"evidence\": \"Postmortem immunohistochemistry, Co-IP in human brain, AAV knockdown with behavioral assays in mice\",\n      \"pmids\": [\"30307500\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Causal direction of spinophilin/synapsin changes not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided patient-derived mechanistic evidence that NOS1AP risk alleles reduce NOS1 expression and co-localization, causing NOS1 loss-of-function electrophysiology and arrhythmia phenotype.\",\n      \"evidence\": \"hiPSC-CMs from LQT1 patients, guinea pig cardiomyocyte NOS1 inhibition, patch-clamp, calcium imaging, AP clamp\",\n      \"pmids\": [\"32061134\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Allele-specific regulatory mechanism on NOS1 expression not fully resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed that excess nNOS-CAPON pairing recruits PSD-95, reduces spine density, and impairs social and working memory, defining a dose-dependent cognitive role.\",\n      \"evidence\": \"AAV overexpression in mouse hippocampus, Co-IP, Golgi spine analysis, behavioral testing\",\n      \"pmids\": [\"34455393\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanism by which CAPON increases nNOS-PSD-95 binding unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Confirmed the cardiac S-nitrosylation mechanism in vivo, showing Nos1ap overexpression increases L-type channel nitrosylation, shortens APD, and is arrhythmogenic.\",\n      \"evidence\": \"Cardiac-specific transgenic mice, patch-clamp, optical mapping, ECG/telemetry, nitrosylation immunochemistry\",\n      \"pmids\": [\"36352324\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"cGMP/ROS-independent nitrosylation route not mechanistically detailed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed NOS1AP downstream of TDP-43, showing it is a direct TDP-43 mRNA target controlling NMDA-receptor signaling and that NOS1AP modulation rescues TDP-43 pathology.\",\n      \"evidence\": \"Transcriptome analysis, Drosophila genetic rescue, primary cortical neuron NMDA signaling assays\",\n      \"pmids\": [\"36267332\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Relevance to human ALS/FTD pathology not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Reported that NOS1AP interacts with and co-aggregates with α-synuclein, implicating it in synucleinopathies.\",\n      \"evidence\": \"Bioinformatic prediction and overexpression in yeast and mammalian cells with co-aggregation assay\",\n      \"pmids\": [\"36012368\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Direct binding not rigorously demonstrated\", \"No in vivo validation\", \"Aggregation shown only by overexpression\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Localized cognitive function of the nNOS/NOS1AP interaction to the medial prefrontal cortex, with disruption selectively impairing social recognition and working memory.\",\n      \"evidence\": \"Stereotaxic AAV manipulation in mouse mPFC with construct controls and behavioral battery\",\n      \"pmids\": [\"36513018\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Downstream signaling in mPFC not dissected\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The high-resolution structural basis of the heterodivalent ExF/PDZ nNOS engagement and the identity of the additional structured element remain unresolved, as does whether the disease-relevant partners (tau, α-synuclein, MKK3) bind through shared or distinct surfaces.\",\n      \"evidence\": \"No structural or domain-resolution study in the corpus addresses these questions\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal/cryo-EM structure of NOS1AP–nNOS\", \"Binding domains for tau and α-synuclein unmapped\", \"Whether neuronal and cardiac functions share regulatory mechanisms unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 2, 5, 7, 11]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 3, 11, 23, 27]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [29]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [19]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [9, 28, 30]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [29]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 7, 10]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 2, 4, 8]},\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [3, 23, 27, 31]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [7, 16, 22]}\n    ],\n    \"complexes\": [\n      \"nNOS–CAPON–Dexras1 ternary complex\",\n      \"nNOS–CAPON–synapsin I complex\",\n      \"Scribble–β-Pix/Git1/PAK complex\",\n      \"SCRIB–VANGL1–NOS1AP complex\"\n    ],\n    \"partners\": [\n      \"NOS1\",\n      \"DEXRAS1\",\n      \"SYN1\",\n      \"SCRIB\",\n      \"CPE\",\n      \"MAP2K3\",\n      \"YAP1\",\n      \"MAPT\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}