{"gene":"IRAG2","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":1994,"finding":"JAW1/LRMP is an integral membrane protein localized to the cytoplasmic face of the endoplasmic reticulum in lymphocytes, anchored via a C-terminal transmembrane domain. In vitro translation with canine microsomes confirmed its ER membrane integration and cytosolic orientation.","method":"Indirect immunofluorescence, confocal microscopy, in vitro translation with canine microsomes, subcellular fractionation","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro reconstitution with microsomes plus direct imaging, replicated across cell types (lymphocytes and HeLa), multiple orthogonal methods in one study","pmids":["8021504"],"is_preprint":false},{"year":1996,"finding":"The C-terminal 71 amino acids of JAW1 are necessary and sufficient for ER targeting. The protein undergoes a novel post-translational cleavage of a short 36 amino acid lumenal domain, generating multiple isoforms with distinct sedimentation properties.","method":"Deletion mutagenesis, in vitro translation, pulse-chase immunoprecipitation, sucrose gradient ultracentrifugation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution, domain mutagenesis, and pulse-chase in a single rigorous study with multiple orthogonal methods","pmids":["8798562"],"is_preprint":false},{"year":2010,"finding":"LRMP/Jaw1 is expressed in sweet, bitter, and umami taste receptor cells and associates with type III IP3 receptor (IP3R3) via its coiled-coil domain in a heterologous expression system.","method":"Co-immunoprecipitation in COS7 cells, in situ hybridization","journal":"Chemical senses","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single co-IP in heterologous system, coiled-coil domain implicated, no in vitro reconstitution","pmids":["20071408"],"is_preprint":false},{"year":2012,"finding":"In zebrafish, the maternal long-form of Lrmp (encoded by futile cycle/fue) localizes to nuclear membranes, centrosomes, and spindles, and is required for male pronucleus-centrosome attachment and female pronuclear migration. C-terminal truncations identified subcellular targeting signals; correct localization of Lrmp protein and mRNA depends on Lrmp function itself.","method":"Genetic mutant analysis (fue zebrafish), live imaging of EGFP fusion proteins, truncation mutant targeting assays","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function genetic mutant with specific cellular phenotype, domain truncation mapping, live imaging, replicated in vivo","pmids":["22542100"],"is_preprint":false},{"year":2018,"finding":"Jaw1/LRMP maintains nuclear shape in mouse melanoma cells. siRNA-mediated knockdown causes severe nuclear shape defects rescued by siRNA-resistant Jaw1. Jaw1 interacts with SUN proteins (inner nuclear membrane) and microtubules, functioning as a KASH-domain protein in the LINC complex.","method":"siRNA knockdown, rescue experiments, co-immunoprecipitation, sequence alignment revealing partial KASH domain homology","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined phenotype and rescue, Co-IP for interaction, single lab","pmids":["29878215"],"is_preprint":false},{"year":2021,"finding":"IRAG2/Jaw1 interacts with IP3 receptor subtypes 1, 2, and 3 in murine pancreatic acinar cells. Loss of IRAG2 decreases basal intracellular Ca2+ levels and alters amylase secretion, indicating IRAG2 promotes IP3R activity under basal conditions.","method":"Co-immunoprecipitation, IRAG2 knockout mice, Ca2+ measurements, amylase secretion assay","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined Ca2+ phenotype and functional readout, Co-IP for interaction, single lab","pmids":["34948204"],"is_preprint":false},{"year":2021,"finding":"The N-terminal intrinsically disordered region (IDR) of Jaw1 prevents aberrant oligomerization via the coiled-coil domain; deletion of this region causes formation of organized smooth ER (OSER) structures and mislocalizes interactors IP3R3 and SUN2. The coiled-coil domain mediates Jaw1 oligomerization.","method":"Co-immunoprecipitation of truncation mutants, fluorescence microscopy of ectopic expression constructs, electron microscopy of OSER","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP domain mapping, overexpression phenotype, multiple interactor readouts, single lab","pmids":["33436890"],"is_preprint":false},{"year":2022,"finding":"IRAG2 is a substrate of cGMP-dependent protein kinase I (PKGI) in murine platelets; it is phosphorylated at Ser/Thr residues upon cGMP stimulation. IRAG2 interacts with IP3R1-3 (by Co-IP) but no stable interaction with PKGIβ or IRAG1 was detected. Loss of IRAG2 reduces platelet aggregation; cGMP pretreatment further reduces aggregation in IRAG2-KO platelets, indicating IRAG2 promotes platelet aggregation in a cGMP/PKGI-dependent manner.","method":"Co-immunoprecipitation, phospho-antibody detection in IRAG2-WT vs KO platelets, platelet aggregation assay with agonists, IRAG2-KO mice","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse, functional aggregation assay, phosphorylation detected, Co-IP, single lab","pmids":["35743138"],"is_preprint":false},{"year":2022,"finding":"Jaw1/LRMP increases cytosolic Ca2+ oscillation amplitude and duration upon GPCR stimulation by modulating IP3R (ITPR) activity, with heterogeneous effects on ITPR1, ITPR2, and ITPR3 subtypes.","method":"Inducible Jaw1-expressing HEK293 cells, Ca2+ imaging upon GPCR stimulation, comparison across ITPR isoforms","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — inducible expression system with defined functional Ca2+ readout, multiple ITPR subtypes tested, single lab","pmids":["35676525"],"is_preprint":false},{"year":2023,"finding":"The C-terminal region of Jaw1 is cleaved post-insertionally by the signal peptidase complex (SPC), specifically by the catalytic subunit SEC11A but not SEC11C. A cleavage-deficient mutant shows reduced augmentation of IP3R-mediated Ca2+ release, demonstrating that cleavage enhances Jaw1's stimulatory effect on IP3Rs.","method":"Mutagenesis of cleavage site, siRNA knockdown of SEC11A vs SEC11C, Ca2+ release assays, mass spectrometry identification of cleavage product","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis of processing site combined with specific enzyme knockdown and functional Ca2+ assay; multiple orthogonal methods in one study","pmids":["36789796"],"is_preprint":false},{"year":2023,"finding":"Jaw1/LRMP knockdown causes Golgi fragmentation with disordered ribbon structure, accompanied by dispersal of the Golgi-derived (acetylated tubulin) microtubule network, identifying Jaw1 as a KASH protein required for Golgi ribbon maintenance.","method":"siRNA knockdown, fluorescence microscopy of Golgi markers, acetylated tubulin imaging","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — KD with defined morphological phenotype and microtubule network readout, single lab","pmids":["36689741"],"is_preprint":false},{"year":2024,"finding":"LRMP specifically inhibits cAMP-dependent potentiation of HCN4 channels (not HCN1/2/3) by disrupting intramolecular signal transduction between cyclic nucleotide binding and channel gating. The first 227 residues of LRMP and the N-terminus of HCN4 are required for their interaction. HCN4 N-terminus and HCN4-specific C-linker residues are required for regulation. LRMP-regulation can be conferred to HCN2 by adding the HCN4 N-terminus and mutating five S5/C-linker residues.","method":"Patch-clamp electrophysiology, FRET, domain deletion/mutagenesis of both LRMP and HCN4, gain-of-function transfer to HCN2","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — electrophysiology with mutagenesis, FRET for interaction, domain mapping, gain-of-function transfer experiment; multiple orthogonal methods in one rigorous study","pmids":["38652113"],"is_preprint":false},{"year":2025,"finding":"Jaw1/LRMP/IRAG2 accelerates the onset time and rise time to the first Ca2+ peak upon GPCR stimulation, particularly in cells expressing ITPR1, in addition to previously described increases in maximum amplitude and retention time.","method":"Ca2+ imaging in HEK293 cells expressing defined ITPR subtypes with and without Jaw1","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined expression system with quantified Ca2+ kinetics, multiple ITPR subtypes, single lab","pmids":["40128249"],"is_preprint":false}],"current_model":"IRAG2/JAW1/LRMP is a tail-anchored type II integral ER membrane protein (C-terminal transmembrane anchor sufficient for ER targeting; N-terminal IDR prevents aberrant oligomerization) that functions as a KASH-domain protein in the LINC complex to maintain nuclear shape and Golgi ribbon structure via interactions with SUN proteins and microtubules, and as a Ca2+ signaling regulator that interacts with IP3 receptor subtypes 1–3 through its coiled-coil domain to augment and accelerate IP3R-mediated Ca2+ release upon GPCR stimulation—a stimulatory activity enhanced by SEC11A-mediated cleavage of its lumenal C-terminal region—while also acting as a specific inhibitor of HCN4 channel cAMP-potentiation by disrupting intramolecular coupling between cyclic nucleotide binding and gating, and serving as a cGMP/PKGI-phosphorylatable substrate that promotes platelet aggregation."},"narrative":{"mechanistic_narrative":"IRAG2 (JAW1/LRMP) is a tail-anchored type II integral membrane protein of the endoplasmic reticulum, integrated via a C-terminal transmembrane anchor that orients its bulk to the cytosol and is necessary and sufficient for ER targeting [PMID:8021504, PMID:8798562]. Its lumenal C-terminal region is removed by post-insertional cleavage carried out by the signal peptidase complex catalytic subunit SEC11A [PMID:8798562, PMID:36789796], and its N-terminal intrinsically disordered region restrains coiled-coil-mediated oligomerization, preventing aberrant organized smooth ER formation and proper positioning of its interactors [PMID:33436890]. Functionally, IRAG2 is a regulator of IP3 receptor-mediated Ca2+ signaling: it binds IP3R subtypes 1–3 through its coiled-coil domain and augments and accelerates IP3R-mediated cytosolic Ca2+ release upon GPCR stimulation, with the SEC11A cleavage event enhancing this stimulatory activity [PMID:20071408, PMID:34948204, PMID:35676525, PMID:36789796, PMID:40128249]. Independently, it serves a structural role as a KASH-domain LINC-complex component that interacts with SUN proteins and microtubules to maintain nuclear shape and Golgi ribbon organization [PMID:29878215, PMID:36689741], and in zebrafish the long maternal form is required for pronucleus and centrosome positioning during early development [PMID:22542100]. IRAG2 also acts as a specific inhibitor of cAMP-dependent potentiation of HCN4 channels by disrupting intramolecular coupling between cyclic nucleotide binding and gating [PMID:38652113], and is a cGMP/PKGI phosphorylation substrate that promotes platelet aggregation [PMID:35743138].","teleology":[{"year":1994,"claim":"Established the basic topology and subcellular home of the protein, defining it as an ER-anchored integral membrane protein facing the cytosol.","evidence":"Immunofluorescence, in vitro translation with canine microsomes, and subcellular fractionation in lymphocytes and HeLa","pmids":["8021504"],"confidence":"High","gaps":["No molecular function assigned","No interacting partners identified"]},{"year":1996,"claim":"Mapped the ER-targeting determinant to the C-terminal 71 residues and revealed a novel post-translational cleavage of a short lumenal domain generating multiple isoforms.","evidence":"Deletion mutagenesis, in vitro translation, pulse-chase immunoprecipitation, sucrose gradient ultracentrifugation","pmids":["8798562"],"confidence":"High","gaps":["Protease responsible for cleavage not identified","Functional consequence of cleavage unknown at this stage"]},{"year":2010,"claim":"First linked the protein to Ca2+ signaling machinery by identifying a coiled-coil-mediated association with IP3R3 in taste receptor cells.","evidence":"Co-immunoprecipitation in COS7 cells and in situ hybridization","pmids":["20071408"],"confidence":"Medium","gaps":["Single co-IP in heterologous system","Functional effect on IP3R activity not tested","No reciprocal validation"]},{"year":2012,"claim":"Demonstrated an in vivo developmental role, showing the maternal long form localizes to nuclear membranes, centrosomes, and spindles and is required for pronucleus-centrosome attachment and pronuclear migration.","evidence":"Zebrafish futile cycle genetic mutant, live imaging of EGFP fusions, truncation targeting assays","pmids":["22542100"],"confidence":"High","gaps":["Molecular mechanism of pronuclear positioning unresolved","Relationship to Ca2+ function not addressed"]},{"year":2018,"claim":"Defined a structural role as a KASH-domain LINC-complex protein maintaining nuclear shape through interactions with SUN proteins and microtubules.","evidence":"siRNA knockdown with rescue, co-immunoprecipitation, KASH domain sequence alignment in mouse melanoma cells","pmids":["29878215"],"confidence":"Medium","gaps":["KASH homology partial; structural basis of SUN binding not solved","Single lab"]},{"year":2021,"claim":"Resolved how the protein avoids aberrant self-assembly, showing the N-terminal IDR suppresses coiled-coil-driven oligomerization to preserve correct ER morphology and interactor localization.","evidence":"Co-IP of truncation mutants, fluorescence microscopy of ectopic constructs, electron microscopy of OSER","pmids":["33436890"],"confidence":"Medium","gaps":["Overexpression-based phenotype","Physiological oligomeric state in vivo unknown"]},{"year":2021,"claim":"Extended IP3R regulation to a physiological context, showing the protein binds IP3R1-3 and promotes basal IP3R activity affecting Ca2+ levels and amylase secretion.","evidence":"Co-IP, IRAG2-knockout mice, Ca2+ measurements, amylase secretion assay in pancreatic acinar cells","pmids":["34948204"],"confidence":"Medium","gaps":["Direct vs indirect IP3R modulation not distinguished","Single lab"]},{"year":2022,"claim":"Established a distinct cGMP/PKGI-dependent role in platelets, identifying the protein as a PKGI substrate that promotes platelet aggregation.","evidence":"Co-IP, phospho-antibody detection in WT vs KO platelets, aggregation assays, IRAG2-KO mice","pmids":["35743138"],"confidence":"Medium","gaps":["Phosphosites not precisely mapped","No stable PKGIbeta or IRAG1 interaction detected, leaving recruitment mechanism unclear"]},{"year":2022,"claim":"Quantified the stimulatory effect on IP3R signaling, showing the protein increases cytosolic Ca2+ oscillation amplitude and duration upon GPCR stimulation with subtype-specific effects.","evidence":"Inducible expression in HEK293 cells, Ca2+ imaging across ITPR isoforms","pmids":["35676525"],"confidence":"Medium","gaps":["Mechanism of subtype heterogeneity unexplained","Single lab"]},{"year":2023,"claim":"Identified the protease and functional purpose of the lumenal cleavage, showing SEC11A (not SEC11C) cleaves the C-terminus and that cleavage enhances IP3R stimulation.","evidence":"Cleavage-site mutagenesis, SEC11A vs SEC11C siRNA, Ca2+ release assays, mass spectrometry","pmids":["36789796"],"confidence":"High","gaps":["Structural basis of cleavage-enhanced IP3R augmentation unknown","Regulation of cleavage timing unaddressed"]},{"year":2023,"claim":"Broadened the structural role to Golgi, showing knockdown fragments the Golgi ribbon and disperses the Golgi-derived microtubule network.","evidence":"siRNA knockdown, fluorescence microscopy of Golgi markers and acetylated tubulin","pmids":["36689741"],"confidence":"Medium","gaps":["Direct molecular link between KASH activity and Golgi tubulin not established","Single lab"]},{"year":2024,"claim":"Revealed a separate ion-channel regulatory function, showing the protein specifically inhibits cAMP potentiation of HCN4 by uncoupling cyclic nucleotide binding from gating.","evidence":"Patch-clamp electrophysiology, FRET, domain mutagenesis of LRMP and HCN4, gain-of-function transfer to HCN2","pmids":["38652113"],"confidence":"High","gaps":["Structural model of the LRMP-HCN4 N-terminus interface lacking","Physiological/cardiac relevance not tested"]},{"year":2025,"claim":"Refined the kinetics of IP3R stimulation, showing the protein accelerates onset and rise time to the first Ca2+ peak, especially with ITPR1.","evidence":"Ca2+ imaging in HEK293 cells expressing defined ITPR subtypes","pmids":["40128249"],"confidence":"Medium","gaps":["Molecular basis of accelerated kinetics unresolved","Single lab"]},{"year":null,"claim":"How the protein's distinct ER-Ca2+, LINC/structural, HCN4-regulatory, and platelet-signaling roles are coordinated within one protein and across tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of full-length protein or its complexes","Whether the coiled-coil simultaneously serves oligomerization, IP3R binding, and SUN/KASH function is unknown","No integrated model linking cleavage state to functional output"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,8,9,11,12]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,4,6]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[4,10]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1,6]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[3,4]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[10]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,8,11,12]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[7]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[4,10]}],"complexes":["LINC complex"],"partners":["ITPR1","ITPR2","ITPR3","SUN2","HCN4","SEC11A","PRKG1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q12912","full_name":"Inositol 1,4,5-triphosphate receptor associated 2","aliases":["Lymphoid-restricted membrane protein","Protein Jaw1"],"length_aa":555,"mass_kda":62.1,"function":"Plays a role in the delivery of peptides to major histocompatibility complex (MHC) class I molecules; this occurs in a transporter associated with antigen processing (TAP)-independent manner. May play a role in taste signal transduction via ITPR3. May play a role during fertilization in pronucleus congression and fusion. Plays a role in maintaining nuclear shape, maybe as a component of the LINC complex and through interaction with microtubules. Plays a role in the regulation of cellular excitability by regulating the hyperpolarization-activated cyclic nucleotide-gated HCN4 channel activity (By similarity)","subcellular_location":"Endoplasmic reticulum membrane; Nucleus envelope; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Cytoplasm, cytoskeleton, spindle pole; Chromosome","url":"https://www.uniprot.org/uniprotkb/Q12912/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IRAG2","classification":"Not Classified","n_dependent_lines":9,"n_total_lines":1208,"dependency_fraction":0.0074503311258278145},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IRAG2","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Endoplasmic reticulum","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":48.7},{"tissue":"lymphoid tissue","ntpm":167.0}],"url":"https://www.proteinatlas.org/search/IRAG2"},"hgnc":{"alias_symbol":["JAW1"],"prev_symbol":["LRMP"]},"alphafold":{"accession":"Q12912","domains":[{"cath_id":"1.10.287","chopping":"203-343","consensus_level":"medium","plddt":92.9323,"start":203,"end":343}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12912","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q12912-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q12912-F1-predicted_aligned_error_v6.png","plddt_mean":58.16},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IRAG2","jax_strain_url":"https://www.jax.org/strain/search?query=IRAG2"},"sequence":{"accession":"Q12912","fasta_url":"https://rest.uniprot.org/uniprotkb/Q12912.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q12912/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12912"}},"corpus_meta":[{"pmid":"8021504","id":"PMC_8021504","title":"Jaw1, A lymphoid-restricted membrane protein localized to the endoplasmic reticulum.","date":"1994","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/8021504","citation_count":67,"is_preprint":false},{"pmid":"22542100","id":"PMC_22542100","title":"Localized products of futile cycle/lrmp promote centrosome-nucleus attachment in the zebrafish zygote.","date":"2012","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/22542100","citation_count":57,"is_preprint":false},{"pmid":"10321731","id":"PMC_10321731","title":"Mrvi1, a common MRV integration site in BXH2 myeloid leukemias, encodes a protein with homology to a lymphoid-restricted membrane protein Jaw1.","date":"1999","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/10321731","citation_count":38,"is_preprint":false},{"pmid":"8798562","id":"PMC_8798562","title":"Carboxyl-terminal targeting and novel post-translational processing of JAW1, a lymphoid protein of the endoplasmic reticulum.","date":"1996","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8798562","citation_count":37,"is_preprint":false},{"pmid":"16739114","id":"PMC_16739114","title":"Jaw1/LRMP, a germinal centre-associated marker for the immunohistological study of B-cell lymphomas.","date":"2006","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/16739114","citation_count":36,"is_preprint":false},{"pmid":"20071408","id":"PMC_20071408","title":"Lrmp/Jaw1 is expressed in sweet, bitter, and umami receptor-expressing cells.","date":"2010","source":"Chemical senses","url":"https://pubmed.ncbi.nlm.nih.gov/20071408","citation_count":33,"is_preprint":false},{"pmid":"29878215","id":"PMC_29878215","title":"Jaw1/LRMP has a role in maintaining nuclear shape via interaction with SUN proteins.","date":"2018","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29878215","citation_count":27,"is_preprint":false},{"pmid":"35201443","id":"PMC_35201443","title":"New immunological potential markers for triple negative breast cancer: IL18R1, CD53, TRIM, Jaw1, LTB, PTPRCAP.","date":"2021","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35201443","citation_count":19,"is_preprint":false},{"pmid":"34948204","id":"PMC_34948204","title":"IRAG2 Interacts with IP3-Receptor Types 1, 2, and 3 and Regulates Intracellular Ca2+ in Murine Pancreatic Acinar Cells.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34948204","citation_count":13,"is_preprint":false},{"pmid":"14563018","id":"PMC_14563018","title":"Lrmp and Bcat1 are candidates for the type I diabetes susceptibility locus Idd6.","date":"2003","source":"Autoimmunity","url":"https://pubmed.ncbi.nlm.nih.gov/14563018","citation_count":12,"is_preprint":false},{"pmid":"36689741","id":"PMC_36689741","title":"Jaw1/LRMP is associated with the maintenance of Golgi ribbon structure.","date":"2023","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36689741","citation_count":11,"is_preprint":false},{"pmid":"16410263","id":"PMC_16410263","title":"A V141L polymorphism of the human LRMP gene is associated with survival of lung cancer patients.","date":"2006","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/16410263","citation_count":11,"is_preprint":false},{"pmid":"35676525","id":"PMC_35676525","title":"Jaw1/LRMP increases Ca2+ influx upon GPCR stimulation with heterogeneous effect on the activity of each ITPR subtype.","date":"2022","source":"Scientific 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mice.","date":"2007","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/17353998","citation_count":5,"is_preprint":false},{"pmid":"38652113","id":"PMC_38652113","title":"LRMP inhibits cAMP potentiation of HCN4 channels by disrupting intramolecular signal transduction.","date":"2024","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/38652113","citation_count":4,"is_preprint":false},{"pmid":"36789796","id":"PMC_36789796","title":"Cleavage of the Jaw1 C-terminal region enhances its augmentative effect on the Ca2+ release via IP3 receptors.","date":"2023","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/36789796","citation_count":3,"is_preprint":false},{"pmid":"35743138","id":"PMC_35743138","title":"Function of IRAG2 Is Modulated by NO/cGMP in Murine Platelets.","date":"2022","source":"International journal of molecular 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profiling of small cell lung cancer reveals subtype heterogeneity and a tuft cell-like subtype characterized by LRMP and TRPM5.","date":"2026","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/41739157","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.17.649313","title":"A Computational Framework for Analysis of cfDNA Fragmentation Profiles","date":"2025-04-18","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.17.649313","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13437,"output_tokens":3225,"usd":0.044343,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10789,"output_tokens":3938,"usd":0.076198,"stage2_stop_reason":"end_turn"},"total_usd":0.120541,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"JAW1/LRMP is an integral membrane protein localized to the cytoplasmic face of the endoplasmic reticulum in lymphocytes, anchored via a C-terminal transmembrane domain. In vitro translation with canine microsomes confirmed its ER membrane integration and cytosolic orientation.\",\n      \"method\": \"Indirect immunofluorescence, confocal microscopy, in vitro translation with canine microsomes, subcellular fractionation\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro reconstitution with microsomes plus direct imaging, replicated across cell types (lymphocytes and HeLa), multiple orthogonal methods in one study\",\n      \"pmids\": [\"8021504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The C-terminal 71 amino acids of JAW1 are necessary and sufficient for ER targeting. The protein undergoes a novel post-translational cleavage of a short 36 amino acid lumenal domain, generating multiple isoforms with distinct sedimentation properties.\",\n      \"method\": \"Deletion mutagenesis, in vitro translation, pulse-chase immunoprecipitation, sucrose gradient ultracentrifugation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution, domain mutagenesis, and pulse-chase in a single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"8798562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"LRMP/Jaw1 is expressed in sweet, bitter, and umami taste receptor cells and associates with type III IP3 receptor (IP3R3) via its coiled-coil domain in a heterologous expression system.\",\n      \"method\": \"Co-immunoprecipitation in COS7 cells, in situ hybridization\",\n      \"journal\": \"Chemical senses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single co-IP in heterologous system, coiled-coil domain implicated, no in vitro reconstitution\",\n      \"pmids\": [\"20071408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In zebrafish, the maternal long-form of Lrmp (encoded by futile cycle/fue) localizes to nuclear membranes, centrosomes, and spindles, and is required for male pronucleus-centrosome attachment and female pronuclear migration. C-terminal truncations identified subcellular targeting signals; correct localization of Lrmp protein and mRNA depends on Lrmp function itself.\",\n      \"method\": \"Genetic mutant analysis (fue zebrafish), live imaging of EGFP fusion proteins, truncation mutant targeting assays\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function genetic mutant with specific cellular phenotype, domain truncation mapping, live imaging, replicated in vivo\",\n      \"pmids\": [\"22542100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Jaw1/LRMP maintains nuclear shape in mouse melanoma cells. siRNA-mediated knockdown causes severe nuclear shape defects rescued by siRNA-resistant Jaw1. Jaw1 interacts with SUN proteins (inner nuclear membrane) and microtubules, functioning as a KASH-domain protein in the LINC complex.\",\n      \"method\": \"siRNA knockdown, rescue experiments, co-immunoprecipitation, sequence alignment revealing partial KASH domain homology\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined phenotype and rescue, Co-IP for interaction, single lab\",\n      \"pmids\": [\"29878215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IRAG2/Jaw1 interacts with IP3 receptor subtypes 1, 2, and 3 in murine pancreatic acinar cells. Loss of IRAG2 decreases basal intracellular Ca2+ levels and alters amylase secretion, indicating IRAG2 promotes IP3R activity under basal conditions.\",\n      \"method\": \"Co-immunoprecipitation, IRAG2 knockout mice, Ca2+ measurements, amylase secretion assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined Ca2+ phenotype and functional readout, Co-IP for interaction, single lab\",\n      \"pmids\": [\"34948204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The N-terminal intrinsically disordered region (IDR) of Jaw1 prevents aberrant oligomerization via the coiled-coil domain; deletion of this region causes formation of organized smooth ER (OSER) structures and mislocalizes interactors IP3R3 and SUN2. The coiled-coil domain mediates Jaw1 oligomerization.\",\n      \"method\": \"Co-immunoprecipitation of truncation mutants, fluorescence microscopy of ectopic expression constructs, electron microscopy of OSER\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP domain mapping, overexpression phenotype, multiple interactor readouts, single lab\",\n      \"pmids\": [\"33436890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IRAG2 is a substrate of cGMP-dependent protein kinase I (PKGI) in murine platelets; it is phosphorylated at Ser/Thr residues upon cGMP stimulation. IRAG2 interacts with IP3R1-3 (by Co-IP) but no stable interaction with PKGIβ or IRAG1 was detected. Loss of IRAG2 reduces platelet aggregation; cGMP pretreatment further reduces aggregation in IRAG2-KO platelets, indicating IRAG2 promotes platelet aggregation in a cGMP/PKGI-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, phospho-antibody detection in IRAG2-WT vs KO platelets, platelet aggregation assay with agonists, IRAG2-KO mice\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse, functional aggregation assay, phosphorylation detected, Co-IP, single lab\",\n      \"pmids\": [\"35743138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Jaw1/LRMP increases cytosolic Ca2+ oscillation amplitude and duration upon GPCR stimulation by modulating IP3R (ITPR) activity, with heterogeneous effects on ITPR1, ITPR2, and ITPR3 subtypes.\",\n      \"method\": \"Inducible Jaw1-expressing HEK293 cells, Ca2+ imaging upon GPCR stimulation, comparison across ITPR isoforms\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — inducible expression system with defined functional Ca2+ readout, multiple ITPR subtypes tested, single lab\",\n      \"pmids\": [\"35676525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The C-terminal region of Jaw1 is cleaved post-insertionally by the signal peptidase complex (SPC), specifically by the catalytic subunit SEC11A but not SEC11C. A cleavage-deficient mutant shows reduced augmentation of IP3R-mediated Ca2+ release, demonstrating that cleavage enhances Jaw1's stimulatory effect on IP3Rs.\",\n      \"method\": \"Mutagenesis of cleavage site, siRNA knockdown of SEC11A vs SEC11C, Ca2+ release assays, mass spectrometry identification of cleavage product\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis of processing site combined with specific enzyme knockdown and functional Ca2+ assay; multiple orthogonal methods in one study\",\n      \"pmids\": [\"36789796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Jaw1/LRMP knockdown causes Golgi fragmentation with disordered ribbon structure, accompanied by dispersal of the Golgi-derived (acetylated tubulin) microtubule network, identifying Jaw1 as a KASH protein required for Golgi ribbon maintenance.\",\n      \"method\": \"siRNA knockdown, fluorescence microscopy of Golgi markers, acetylated tubulin imaging\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — KD with defined morphological phenotype and microtubule network readout, single lab\",\n      \"pmids\": [\"36689741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LRMP specifically inhibits cAMP-dependent potentiation of HCN4 channels (not HCN1/2/3) by disrupting intramolecular signal transduction between cyclic nucleotide binding and channel gating. The first 227 residues of LRMP and the N-terminus of HCN4 are required for their interaction. HCN4 N-terminus and HCN4-specific C-linker residues are required for regulation. LRMP-regulation can be conferred to HCN2 by adding the HCN4 N-terminus and mutating five S5/C-linker residues.\",\n      \"method\": \"Patch-clamp electrophysiology, FRET, domain deletion/mutagenesis of both LRMP and HCN4, gain-of-function transfer to HCN2\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — electrophysiology with mutagenesis, FRET for interaction, domain mapping, gain-of-function transfer experiment; multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"38652113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Jaw1/LRMP/IRAG2 accelerates the onset time and rise time to the first Ca2+ peak upon GPCR stimulation, particularly in cells expressing ITPR1, in addition to previously described increases in maximum amplitude and retention time.\",\n      \"method\": \"Ca2+ imaging in HEK293 cells expressing defined ITPR subtypes with and without Jaw1\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined expression system with quantified Ca2+ kinetics, multiple ITPR subtypes, single lab\",\n      \"pmids\": [\"40128249\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IRAG2/JAW1/LRMP is a tail-anchored type II integral ER membrane protein (C-terminal transmembrane anchor sufficient for ER targeting; N-terminal IDR prevents aberrant oligomerization) that functions as a KASH-domain protein in the LINC complex to maintain nuclear shape and Golgi ribbon structure via interactions with SUN proteins and microtubules, and as a Ca2+ signaling regulator that interacts with IP3 receptor subtypes 1–3 through its coiled-coil domain to augment and accelerate IP3R-mediated Ca2+ release upon GPCR stimulation—a stimulatory activity enhanced by SEC11A-mediated cleavage of its lumenal C-terminal region—while also acting as a specific inhibitor of HCN4 channel cAMP-potentiation by disrupting intramolecular coupling between cyclic nucleotide binding and gating, and serving as a cGMP/PKGI-phosphorylatable substrate that promotes platelet aggregation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IRAG2 (JAW1/LRMP) is a tail-anchored type II integral membrane protein of the endoplasmic reticulum, integrated via a C-terminal transmembrane anchor that orients its bulk to the cytosol and is necessary and sufficient for ER targeting [#0, #1]. Its lumenal C-terminal region is removed by post-insertional cleavage carried out by the signal peptidase complex catalytic subunit SEC11A [#1, #9], and its N-terminal intrinsically disordered region restrains coiled-coil-mediated oligomerization, preventing aberrant organized smooth ER formation and proper positioning of its interactors [#6]. Functionally, IRAG2 is a regulator of IP3 receptor-mediated Ca2+ signaling: it binds IP3R subtypes 1\\u20133 through its coiled-coil domain and augments and accelerates IP3R-mediated cytosolic Ca2+ release upon GPCR stimulation, with the SEC11A cleavage event enhancing this stimulatory activity [#2, #5, #8, #9, #12]. Independently, it serves a structural role as a KASH-domain LINC-complex component that interacts with SUN proteins and microtubules to maintain nuclear shape and Golgi ribbon organization [#4, #10], and in zebrafish the long maternal form is required for pronucleus and centrosome positioning during early development [#3]. IRAG2 also acts as a specific inhibitor of cAMP-dependent potentiation of HCN4 channels by disrupting intramolecular coupling between cyclic nucleotide binding and gating [#11], and is a cGMP/PKGI phosphorylation substrate that promotes platelet aggregation [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established the basic topology and subcellular home of the protein, defining it as an ER-anchored integral membrane protein facing the cytosol.\",\n      \"evidence\": \"Immunofluorescence, in vitro translation with canine microsomes, and subcellular fractionation in lymphocytes and HeLa\",\n      \"pmids\": [\"8021504\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No molecular function assigned\", \"No interacting partners identified\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Mapped the ER-targeting determinant to the C-terminal 71 residues and revealed a novel post-translational cleavage of a short lumenal domain generating multiple isoforms.\",\n      \"evidence\": \"Deletion mutagenesis, in vitro translation, pulse-chase immunoprecipitation, sucrose gradient ultracentrifugation\",\n      \"pmids\": [\"8798562\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Protease responsible for cleavage not identified\", \"Functional consequence of cleavage unknown at this stage\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"First linked the protein to Ca2+ signaling machinery by identifying a coiled-coil-mediated association with IP3R3 in taste receptor cells.\",\n      \"evidence\": \"Co-immunoprecipitation in COS7 cells and in situ hybridization\",\n      \"pmids\": [\"20071408\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single co-IP in heterologous system\", \"Functional effect on IP3R activity not tested\", \"No reciprocal validation\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated an in vivo developmental role, showing the maternal long form localizes to nuclear membranes, centrosomes, and spindles and is required for pronucleus-centrosome attachment and pronuclear migration.\",\n      \"evidence\": \"Zebrafish futile cycle genetic mutant, live imaging of EGFP fusions, truncation targeting assays\",\n      \"pmids\": [\"22542100\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of pronuclear positioning unresolved\", \"Relationship to Ca2+ function not addressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined a structural role as a KASH-domain LINC-complex protein maintaining nuclear shape through interactions with SUN proteins and microtubules.\",\n      \"evidence\": \"siRNA knockdown with rescue, co-immunoprecipitation, KASH domain sequence alignment in mouse melanoma cells\",\n      \"pmids\": [\"29878215\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"KASH homology partial; structural basis of SUN binding not solved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved how the protein avoids aberrant self-assembly, showing the N-terminal IDR suppresses coiled-coil-driven oligomerization to preserve correct ER morphology and interactor localization.\",\n      \"evidence\": \"Co-IP of truncation mutants, fluorescence microscopy of ectopic constructs, electron microscopy of OSER\",\n      \"pmids\": [\"33436890\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression-based phenotype\", \"Physiological oligomeric state in vivo unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended IP3R regulation to a physiological context, showing the protein binds IP3R1-3 and promotes basal IP3R activity affecting Ca2+ levels and amylase secretion.\",\n      \"evidence\": \"Co-IP, IRAG2-knockout mice, Ca2+ measurements, amylase secretion assay in pancreatic acinar cells\",\n      \"pmids\": [\"34948204\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect IP3R modulation not distinguished\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established a distinct cGMP/PKGI-dependent role in platelets, identifying the protein as a PKGI substrate that promotes platelet aggregation.\",\n      \"evidence\": \"Co-IP, phospho-antibody detection in WT vs KO platelets, aggregation assays, IRAG2-KO mice\",\n      \"pmids\": [\"35743138\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphosites not precisely mapped\", \"No stable PKGIbeta or IRAG1 interaction detected, leaving recruitment mechanism unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Quantified the stimulatory effect on IP3R signaling, showing the protein increases cytosolic Ca2+ oscillation amplitude and duration upon GPCR stimulation with subtype-specific effects.\",\n      \"evidence\": \"Inducible expression in HEK293 cells, Ca2+ imaging across ITPR isoforms\",\n      \"pmids\": [\"35676525\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of subtype heterogeneity unexplained\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified the protease and functional purpose of the lumenal cleavage, showing SEC11A (not SEC11C) cleaves the C-terminus and that cleavage enhances IP3R stimulation.\",\n      \"evidence\": \"Cleavage-site mutagenesis, SEC11A vs SEC11C siRNA, Ca2+ release assays, mass spectrometry\",\n      \"pmids\": [\"36789796\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of cleavage-enhanced IP3R augmentation unknown\", \"Regulation of cleavage timing unaddressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Broadened the structural role to Golgi, showing knockdown fragments the Golgi ribbon and disperses the Golgi-derived microtubule network.\",\n      \"evidence\": \"siRNA knockdown, fluorescence microscopy of Golgi markers and acetylated tubulin\",\n      \"pmids\": [\"36689741\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between KASH activity and Golgi tubulin not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a separate ion-channel regulatory function, showing the protein specifically inhibits cAMP potentiation of HCN4 by uncoupling cyclic nucleotide binding from gating.\",\n      \"evidence\": \"Patch-clamp electrophysiology, FRET, domain mutagenesis of LRMP and HCN4, gain-of-function transfer to HCN2\",\n      \"pmids\": [\"38652113\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural model of the LRMP-HCN4 N-terminus interface lacking\", \"Physiological/cardiac relevance not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Refined the kinetics of IP3R stimulation, showing the protein accelerates onset and rise time to the first Ca2+ peak, especially with ITPR1.\",\n      \"evidence\": \"Ca2+ imaging in HEK293 cells expressing defined ITPR subtypes\",\n      \"pmids\": [\"40128249\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of accelerated kinetics unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the protein's distinct ER-Ca2+, LINC/structural, HCN4-regulatory, and platelet-signaling roles are coordinated within one protein and across tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of full-length protein or its complexes\", \"Whether the coiled-coil simultaneously serves oligomerization, IP3R binding, and SUN/KASH function is unknown\", \"No integrated model linking cleavage state to functional output\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 8, 9, 11, 12]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 4, 6]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [4, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 8, 11, 12]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [4, 10]}\n    ],\n    \"complexes\": [\"LINC complex\"],\n    \"partners\": [\"ITPR1\", \"ITPR2\", \"ITPR3\", \"SUN2\", \"HCN4\", \"SEC11A\", \"PRKG1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}