Affinage

PCSK1N

ProSAAS · UniProt Q9UHG2

Length
260 aa
Mass
27.4 kDa
Annotated
2026-04-29
100 papers in source corpus 25 papers cited in narrative 25 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PCSK1N encodes proSAAS, a neuroendocrine secretory precursor that serves dual roles as a potent competitive inhibitor of prohormone convertase 1/3 (PC1/3) and as a precursor to bioactive neuropeptides regulating feeding, circadian rhythms, and psychostimulant sensitization. The C-terminal segment of proSAAS contains a hexapeptide that competitively inhibits PC1/3 with nanomolar affinity (Ki ~9–40 nM), while the N-terminal domain independently reduces PC1/3 activity through a distinct mechanism; initial cleavage by furin in the Golgi/TGN generates fragments (PEN, big LEN, little SAAS, little LEN) that are sorted into regulated secretory granules and further processed by PC2 and carboxypeptidase E (PMID:10632593, PMID:10816562, PMID:25148519, PMID:11094058). ProSAAS-derived peptide PEN signals through GPR83 and big LEN through GPR171 to regulate hypothalamic feeding circuits and behavioral sensitization to psychostimulants, while the transcription factor Pax6 directly represses PCSK1N to control proinsulin processing via PC1/3 in pancreatic beta cells (PMID:27117253, PMID:28881029, PMID:23056534). ProSAAS also functions as an anti-amyloid chaperone that blocks fibrillation and cytotoxicity of Aβ, α-synuclein, and hIAPP through its N-terminal/central domain, and lentiviral proSAAS delivery protects nigral dopaminergic neurons and reduces α-synuclein pathology and spread in rodent Parkinson's disease models (PMID:24102330, PMID:27457957, PMID:35527562).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2000 High

    The discovery that proSAAS is a granin-like PC1 inhibitor that blocks POMC processing and is secreted via the regulated pathway established PCSK1N as an endogenous regulator of prohormone conversion.

    Evidence In vitro enzyme inhibition assays with purified proSAAS, overexpression in AtT-20 cells with POMC processing readout

    PMID:10632593

    Open questions at the time
    • Mechanism of selectivity for PC1 over PC2 not structurally resolved
    • No in vivo loss-of-function data at this stage
  2. 2000 High

    Mapping the inhibitory domain to a C-terminal hexapeptide-containing segment with Ki values of 9–40 nM and demonstrating competitive, slow-binding, pH-dependent kinetics defined proSAAS as a secretory-granule-compartment-specific PC1/3 inhibitor.

    Evidence Systematic synthetic peptide inhibition assays, alanine scanning, GST pulldown with PC1 forms, kinetic analysis across multiple labs

    PMID:10812060 PMID:10816562 PMID:11435430

    Open questions at the time
    • No crystal structure of the proSAAS–PC1/3 complex
    • Slow-binding mechanism not fully explained at the structural level
  3. 2000 High

    Identifying proSAAS processing products (little SAAS, PEN, big LEN) in mouse brain and showing impaired processing in Cpe(fat/fat) mice revealed that carboxypeptidase E trims proSAAS-derived peptides and that incompletely processed intermediates retain PC1 inhibitory activity.

    Evidence RIA, RP-HPLC, mass spectrometry on wild-type and Cpe(fat/fat) mouse brain/pituitary

    PMID:11094058

    Open questions at the time
    • Physiological consequences of accumulated PC1-inhibitory intermediates in Cpe-null context not tested
  4. 2001 Medium

    Demonstrating that the N-terminal domain of proSAAS (residues 1–180) reduces secreted PC1 activity independently of the C-terminal inhibitory peptide suggested a second mechanism of PC1 regulation, possibly involving chaperone-like or sorting effects.

    Evidence Cotransfection of N-terminal deletion constructs in HEK293, CHO/PC1, and AtT-20 cells with PC1 activity readout

    PMID:11719503

    Open questions at the time
    • Molecular mechanism of N-terminal-mediated PC1 inactivation not identified
    • No binding partner or structural basis established
  5. 2002 High

    Showing that proSAAS processing in PC12 cells (which lack PC1 and PC2) produces the same peptides as neuroendocrine AtT-20 cells established furin-like enzymes as the initiators of proSAAS cleavage in the Golgi/TGN, upstream of secretory granule convertases.

    Evidence Pulse-chase, mass spectrometry, RP-HPLC, secretagogue stimulation in AtT-20 and PC12 cells

    PMID:11742530

    Open questions at the time
    • Specific furin-family member responsible not definitively identified in vivo
  6. 2010 High

    ProSAAS knockout mice revealed that proSAAS inhibits PC1/3 in embryonic brain in vivo (prodynorphin is prematurely fully processed in fetal KO brain) but is largely dispensable for adult neuropeptide processing, while uncovering behavioral roles (reduced locomotion, male-specific body weight decrease).

    Evidence Targeted gene knockout mouse, peptidomics, RIA, open-field locomotion, glucose tolerance test

    PMID:20367757

    Open questions at the time
    • Compensatory mechanisms in adult KO not characterized
    • Neuropeptide receptor mediating locomotor phenotype unknown at this point
  7. 2012 High

    Identifying Pax6 as a direct transcriptional repressor of PCSK1N that controls PC1/3 activity and proinsulin processing placed proSAAS within a defined transcriptional circuit governing pancreatic beta-cell function.

    Evidence ChIP, EMSA, luciferase reporters, RNAi, and genetic rescue in MIN6 cells

    PMID:23056534

    Open questions at the time
    • In vivo validation in Pax6-haploinsufficient or beta-cell-specific Pcsk1n KO mice not performed
    • Other transcriptional regulators of PCSK1N not surveyed
  8. 2013 High

    Demonstrating that proSAAS blocks fibrillation and cytotoxicity of both Aβ(1-42) and hIAPP, and mapping anti-aggregation activity to the N-terminal/central domain (residues 97–180), established proSAAS as an intracellular anti-amyloid chaperone.

    Evidence ThT fibrillation assays, deletion mutagenesis, co-IP from APdE9 mouse brain, cell viability assays in Neuro2A and Rin5f cells

    PMID:24042052 PMID:24102330

    Open questions at the time
    • Structural basis of anti-aggregation activity unknown
    • In vivo relevance in Alzheimer's or type 2 diabetes models not tested at this stage
  9. 2014 High

    Site-directed mutagenesis of furin consensus sites in proSAAS altered vesicular sorting of PEN and SAAS fragments, establishing that furin-mediated cleavage in the Golgi/TGN directs differential sorting of proSAAS-derived peptides into distinct secretory vesicle populations.

    Evidence Furin site mutagenesis, transfection in AtT-20 cells, confocal colocalization analysis

    PMID:25148519

    Open questions at the time
    • Identity of sorting receptors that distinguish PEN-containing from SAAS-containing vesicles unknown
  10. 2016 High

    Deorphanizing GPR83 as the receptor for PEN, and showing that GPR83 and GPR171 (big LEN receptor) functionally interact when coexpressed, established a dual neuropeptide signaling system derived entirely from a single proSAAS precursor.

    Evidence Radioligand binding, GPR83 knockdown, signaling assays in Neuro2A cells, receptor coexpression

    PMID:27117253

    Open questions at the time
    • Downstream signaling cascades of PEN-GPR83 in hypothalamic neurons not fully mapped
    • In vivo confirmation via GPR83 KO with PEN challenge not yet reported
  11. 2016 High

    Extending the anti-amyloid function to α-synuclein, with mapping of the critical domain (residues 158–180) and demonstration of neuroprotection in primary dopaminergic neurons, positioned proSAAS as a potential therapeutic for synucleinopathies.

    Evidence ThT assay, deletion mutagenesis, lentiviral delivery in primary nigral cultures, immunohistochemistry on human PD substantia nigra

    PMID:27457957

    Open questions at the time
    • Mechanism of chaperone action (holdase vs. sequestration) not resolved
    • Stoichiometry in vivo unknown
  12. 2017 High

    ProSAAS knockout mice failed to sensitize to cocaine and amphetamine while retaining reward responses, dissecting proSAAS-derived neuropeptide function into sensitization (dependent) versus reward (independent) behavioral components.

    Evidence Quantitative peptidomics in nucleus accumbens and VTA, KO mouse locomotor sensitization and conditioned place preference

    PMID:28881029

    Open questions at the time
    • Which specific proSAAS-derived peptide(s) and receptor(s) mediate sensitization not determined
    • Circuit-level mechanism not mapped
  13. 2022 High

    In vivo lentiviral proSAAS delivery protected nigral dopaminergic neurons from α-synuclein toxicity and reduced transsynaptic α-synuclein spread in two independent rodent models, providing preclinical validation of the anti-amyloid chaperone function.

    Evidence Lentiviral/AAV delivery in rat substantia nigra and mouse vagus nerve models, stereology, TH densitometry, behavioral motor tests

    PMID:35527562

    Open questions at the time
    • Long-term efficacy and dose-response not established
    • Mechanism of reduced spread (extracellular chaperone vs. intracellular degradation) not distinguished

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of proSAAS interaction with both PC1/3 and amyloidogenic substrates, the identity of sorting receptors directing proSAAS-derived peptides to distinct vesicle populations, and the circuit-level mechanisms by which PEN/GPR83 and bigLEN/GPR171 regulate behavior remain unresolved.
  • No crystal or cryo-EM structure of proSAAS or its complexes
  • Sorting receptor for proSAAS-derived peptide vesicles not identified
  • Circuit-specific functions of PEN vs. big LEN signaling not dissected

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0044183 protein folding chaperone 4 GO:0048018 receptor ligand activity 1
Localization
GO:0005576 extracellular region 3 GO:0031410 cytoplasmic vesicle 3 GO:0005794 Golgi apparatus 2
Pathway
R-HSA-392499 Metabolism of proteins 6 R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 2
Partners
CPEFURINGPR83PAX6PCSK1PCSK2

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 ProSAAS (encoded by PCSK1N) is a granin-like neuroendocrine peptide precursor that inhibits prohormone convertase 1 (PC1) with an IC50 of 590 nM but does not inhibit PC2; overexpression in AtT-20 cells substantially reduces processing of the endogenous prohormone POMC, and proSAAS is secreted via the regulated pathway. In vitro enzyme inhibition assay with purified proSAAS; overexpression in AtT-20 cells with POMC processing readout; Western blot and radioimmunoassay The Journal of Neuroscience High 10632593
2000 The PC1 inhibitory region of proSAAS maps to an 8–12 residue segment near the C terminus containing a critical Lys-Arg sequence; synthetic peptides from this region are competitive inhibitors of PC1 with Ki values of 14–40 nM; inhibition is slow-binding and pH-dependent (pH 5.5 but not 7.4); a GST fusion containing the inhibitory region binds the 71-kDa but not the 85-kDa form of PC1; proSAAS does not inhibit furin, PACE4, PC5A, or PC7. Synthetic peptide inhibition assays, GST pulldown with PC1 forms, in vitro kinetic analysis The Journal of Biological Chemistry High 10816562
2000 The SAAS C-terminal peptide (SAAS CT) contains a hexapeptide sequence that accounts for the vast majority of proSAAS inhibitory potency toward PC1; nanomolar inhibition constants were established; recombinant PC1 can cleave the SAAS CT peptide at a site consistent with cleavage following the inhibitory hexapeptide, indicating that PC1 can process its own inhibitor. Competitive enzyme inhibition assays, in vitro cleavage with recombinant PC1 FEBS Letters High 10812060
2000 In wild-type mouse brain and pituitary, proSAAS is processed into smaller peptides including little SAAS, PEN, and big LEN; processing is partially impaired in Cpe(fat/fat) mice lacking carboxypeptidase E, leading to accumulation of C-terminally extended PEN, which inhibits PC1 activity. Radioimmunoassay, reverse-phase HPLC, mass spectrometry, gel filtration on wild-type and Cpe(fat/fat) mouse tissues The Journal of Biological Chemistry High 11094058
2001 The decapeptide proSAAS-(235–244) (VLGALLRVKR) is the most potent competitive PC1 inhibitor (Ki ~9 nM); systematic alanine scanning identified P1 Arg, P2 Lys, and P4 Arg as critical for inhibition; the extended proSAAS-(235–246) is a substrate cleaved by PC1 at KR(244); molecular modeling indicates an extended/poly-l-proline II conformation for the most potent inhibitor. In vitro enzyme inhibition assays, alanine scanning mutagenesis of synthetic peptides, circular dichroism, molecular modeling The Journal of Biological Chemistry High 11435430
2001 PC2 or furin can cleave the proSAAS C-terminal peptide in vitro; in PC2 null mouse brains, the proSAAS C-terminal peptide is not processed as efficiently as in wild-type, indicating PC2 is partially responsible for this cleavage in vivo. In vitro cleavage assays with recombinant PC2 and furin, radioimmunoassay on PC2 null mouse brain extracts Journal of Neurochemistry High 11259501
2001 The N-terminal domain of proSAAS (residues 1–180) lacks the inhibitory C-terminal peptide but still reduces PC1 activity detected in medium when co-expressed in HEK293 or CHO/PC1 cells, suggesting a proSAAS-mediated inactivation mechanism distinct from C-terminal competitive inhibition; proSAAS-(1-225) slows processing of proopiomelanocortin and proenkephalin in AtT-20 cells without depleting processed peptide stores. Transient and stable cotransfection in HEK293, CHO/PC1, and AtT-20 cells; PC1 activity assays; pulse-chase The Journal of Biological Chemistry Medium 11719503
2001 ProSAAS-derived peptides (SAAS and LEN) are distributed throughout rat brain and co-localize with PC1 in hippocampus, cerebellum, spinal cord, pituitary, and adrenal medulla; in pancreatic islets, SAAS and LEN are enriched in peripheral (alpha/delta) cells while PC1 is in beta cells, suggesting proSAAS may perform functions beyond PC1 inhibition in some cell types. Immunohistochemistry with antisera to proSAAS-derived peptides and PC1 in rat tissues Neuroscience Medium 11672612
2002 Processing of proSAAS in AtT-20 and PC12 cells produces little SAAS, PEN, and big LEN peptides via the regulated secretory pathway (secretion stimulated by secretagogues); cleavage does not require PC1 or PC2 (PC12 cells express neither), implying a furin-like enzyme mediates initial processing; long-term secretagogue treatment increases PC1 mRNA without affecting proSAAS mRNA, demonstrating independent regulation. Pulse-chase with [3H]leucine, mass spectrometry, reverse-phase HPLC, radioimmunoassay, secretagogue stimulation in AtT-20 and PC12 cells The Biochemical Journal High 11742530
2002 ProSAAS (encoded by mouse gene Pcsk1n) is broadly expressed during mouse development from E9, with expression in neural tube-derived tissues early and later restricted to neuroendocrine tissues; expression pattern generally overlaps with PC1, consistent with a role as endogenous PC1 inhibitor during development. Immunohistochemistry with antisera to SAAS and PC1 in mouse embryos E9–E15 Brain Research Gene Expression Patterns Low 15018810
2004 In AtT-20 cells, proSAAS expression inhibits both C-terminal PC1 processing and POMC processing under pulse-chase conditions; SAAS CT peptide-propeptide chimeric constructs inhibit zymogen processing in HEK293 cells but not in AtT-20 cells; the PC1 propeptide expressed in trans reduces PC1 C-terminal processing and POMC processing. Pulse-chase analysis in AtT-20 and HEK293 cells; transient and stable transfection The Journal of Endocrinology Medium 15283695
2008 ProSAAS orthologs in Xenopus and zebrafish share two conserved 14–16 residue hydrophobic segments predicted to form alpha-helices and two conserved basic convertase cleavage site sequences; both non-mammalian proSAAS proteins inhibit mouse PC1/3 with nanomolar Ki values but not human furin, and are cleaved by PC2 and furin in vitro; both exhibit neural and endocrine tissue distributions. In vitro enzyme inhibition assays, in vitro cleavage assays with recombinant convertases, sequence alignment, in situ hybridization, PCR Endocrinology High 18948394
2010 In fetal proSAAS knockout mice, prodynorphin undergoes complete adult-like processing instead of the incomplete processing seen in wild-type fetuses where proSAAS intermediates transiently accumulate, demonstrating proSAAS directly inhibits PC1/3 in embryonic brain in vivo; adult proSAAS knockout mice show normal neuropeptide levels but decreased locomotion and male-specific ~10–15% body weight decrease, suggesting adult roles as neuropeptides. Targeted gene knockout mouse model, peptidomics, radioimmunoassay, open-field locomotion testing, glucose tolerance test Journal of Neurochemistry High 20367757
2010 Little SAAS (a proSAAS-derived peptide) is expressed in the densely retinorecipient central SCN, colocalizes with VIP and GRP, and blockade of NMDA receptors or VIP/GRP cognate receptors does not affect little SAAS-induced phase delays of circadian rhythms, placing little SAAS downstream of light/glutamatergic signaling but independent of VIP/GRP action. Immunohistochemistry with stereological analysis, c-FOS induction, glutamate-stimulated SCN slice recordings, pharmacological blockade PloS One Medium 20830308
2011 Intracerebroventricular injection of antibodies to PEN and big LEN significantly reduces food intake in fasted mice; big LEN produces rapid and reversible inhibition of synaptic glutamate release in hypothalamic paraventricular nucleus neurons in a manner abolished by blocking postsynaptic G protein activity, suggesting involvement of a postsynaptic GPCR and retrograde synaptic messenger. ICV antibody injection with food intake readout in mice; whole-cell patch clamp of parvocellular neurons with G-protein blockade PloS One High 22164236
2012 Pax6 directly binds the Pcsk1n promoter and down-regulates proSAAS (PCSK1N) expression; Pax6 deficiency increases Pcsk1n expression, which in turn reduces PC1/3 C-terminal processing and activity, impairing proinsulin processing; co-knockdown of Pax6 and Pcsk1n rescues proinsulin processing, placing proSAAS downstream of Pax6 in the regulation of glucose metabolism. Luciferase reporter assays, chromatin immunoprecipitation, EMSA, quantitative RT-PCR, RNAi in MIN6 cells, rescue co-transfection experiments PloS One High 23056534
2013 ProSAAS efficiently prevents fibrillation of Aβ(1-42) in vitro at molar ratios of 1:10; residues 97–180 are sufficient for anti-aggregation activity against Aβ; recombinant proSAAS in medium and lentiviral proSAAS overexpression both block Aβ(1-42)-induced neurocytotoxicity in Neuro2A cells; proSAAS co-immunoprecipitates with Aβ immunoreactivity in APdE9 mouse brain lysates. In vitro fibrillation assay (ThT fluorescence), deletion mutagenesis, co-immunoprecipitation from mouse brain, cell viability assay with Neuro2A cells, lentiviral overexpression Journal of Neurochemistry High 24102330
2013 ProSAAS blocks fibrillation of human islet amyloid polypeptide (hIAPP) in vitro and blocks hIAPP-induced cytotoxicity on Rin5f cells; structure-function studies identified the N-terminal region of proSAAS as important for this anti-aggregation activity; overexpression of proSAAS in cells also blocks hIAPP cytotoxicity. In vitro ThT fibrillation assay, cell viability assays, proSAAS overexpression in cells FEBS Letters Medium 24042052
2014 ProSAAS-derived peptides PEN and big LEN colocalize with neuropeptide Y in mouse hypothalamus; initial proSAAS cleavage is mediated by furin (and/or furin-like enzymes) in the Golgi/TGN, generating fragments sorted into distinct vesicles for further processing; mutation of furin consensus sites (P4 Arg→Lys) in proSAAS dramatically increased colocalization of PEN and SAAS in AtT-20 cells. Immunohistochemistry, site-directed mutagenesis of proSAAS furin sites, transfection of mutant proSAAS in AtT-20 cells, confocal colocalization PloS One High 25148519
2016 PEN (a proSAAS-derived peptide) binds to and activates GPR83, a GPCR in mouse hypothalamus and Neuro2A cells; reduction of GPR83 expression reduces PEN binding and signaling; in brain regions where GPR83 colocalizes with GPR171 (the bigLEN receptor), coexpression alters signaling properties of each receptor, suggesting functional coupling of the two proSAAS-derived neuropeptide systems. Radioligand binding assays, GPR83 knockdown, signaling assays in Neuro2A cells, colocalization by immunofluorescence, receptor coexpression in cell lines Science Signaling High 27117253
2016 ProSAAS potently inhibits α-synuclein fibrillation in vitro; residues 158–180 (containing a largely conserved element) are critical for this bioactivity; proSAAS-encoding lentivirus blocks α-synuclein-induced cytotoxicity in primary nigral dopaminergic neurons; recombinant proSAAS blocks α-synuclein cytotoxicity in SH-SY5Y cells; proSAAS immunoreactivity is associated with aggregated synuclein deposits in Parkinson's disease substantia nigra. In vitro ThT fibrillation assay, deletion mutagenesis, lentiviral delivery in primary dopaminergic cultures, cell viability assay in SH-SY5Y, immunohistochemistry on human PD brain Proceedings of the National Academy of Sciences High 27457957
2017 ProSAAS-derived peptides (big LEN, PEN, little LEN, little SAAS) are decreased in nucleus accumbens and ventral tegmental area following repeated cocaine administration; proSAAS knockout mice fail to sensitize to cocaine and show diminished locomotor sensitization to amphetamine, while conditioned place preference to cocaine is intact, indicating proSAAS peptides contribute to behavioral sensitization but not reward. Quantitative peptidomics in mouse brain regions, proSAAS knockout mice, open-field locomotion and sensitization tests, conditioned place preference Journal of Neurochemistry High 28881029
2019 Neuropeptide PEN-GPR83 signaling is implicated in feeding and body weight regulation; GPR83 distribution overlaps with GPR171 (bigLEN receptor) in some brain regions; coexpression alters receptor signaling, supporting a functionally coupled dual neuropeptide system derived from proSAAS (PCSK1N). Review synthesizing binding assays, knockdown, colocalization, and signaling studies from earlier work ACS Chemical Neuroscience Medium 30726666
2020 Exposure of Neuro2A cells to ER stressors (tunicamycin, thapsigargin), hypoxic stressor (cobalt chloride), or oxidative stressor (sodium arsenite) increases cellular proSAAS mRNA and protein while paradoxically reducing proSAAS secretion, identifying proSAAS as a stress-responsive secretory chaperone. qRT-PCR, Western blot, ELISA for secreted proSAAS following stressor treatment in Neuro2A cells Cell Stress & Chaperones Medium 32607937
2022 Lentiviral proSAAS overexpression in rat substantia nigra profoundly reduces motor asymmetry caused by AAV-mediated human α-synuclein overexpression, accompanied by preservation of nigral TH-positive cells and striatal TH-positive terminals; proSAAS reduces human α-synuclein levels in nigra and striatum; proSAAS also reduces transsynaptic spread of α-synuclein following vagal AAV injection in mice. Lentiviral/AAV delivery in rat/mouse models, nigral stereology, TH densitometry, immunohistochemistry, behavioral motor battery Journal of Parkinson's Disease High 35527562

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex. Neuron 807 12691659
2003 Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2. Proceedings of the National Academy of Sciences of the United States of America 655 12740439
2002 PEN-2 is an integral component of the gamma-secretase complex required for coordinated expression of presenilin and nicastrin. The Journal of biological chemistry 244 12198112
2004 Nicastrin, presenilin, APH-1, and PEN-2 form active gamma-secretase complexes in mitochondria. The Journal of biological chemistry 209 15456764
2000 Identification and characterization of proSAAS, a granin-like neuroendocrine peptide precursor that inhibits prohormone processing. The Journal of neuroscience : the official journal of the Society for Neuroscience 206 10632593
2008 Inteferons pen the JAK-STAT pathway. Seminars in cell & developmental biology 203 18765289
2003 Proteomics and immunological analysis of a novel shrimp allergen, Pen m 2. Journal of immunology (Baltimore, Md. : 1950) 192 12496430
2002 Identification of continuous, allergenic regions of the major shrimp allergen Pen a 1 (tropomyosin). International archives of allergy and immunology 151 11893851
2004 Detergent-dependent dissociation of active gamma-secretase reveals an interaction between Pen-2 and PS1-NTF and offers a model for subunit organization within the complex. Biochemistry 113 14717586
2004 Requirement of PEN-2 for stabilization of the presenilin N-/C-terminal fragment heterodimer within the gamma-secretase complex. The Journal of biological chemistry 104 15039426
2020 Evolution of Dip-Pen Nanolithography (DPN): From Molecular Patterning to Materials Discovery. Chemical reviews 100 32319753
2008 Multiplexed lipid dip-pen nanolithography on subcellular scales for the templating of functional proteins and cell culture. Small (Weinheim an der Bergstrasse, Germany) 98 18814174
2006 Pen ch 13 allergen induces secretion of mediators and degradation of occludin protein of human lung epithelial cells. Allergy 95 16436150
2000 The C-terminal region of proSAAS is a potent inhibitor of prohormone convertase 1. The Journal of biological chemistry 82 10816562
2003 Membrane topology of gamma-secretase component PEN-2. The Journal of biological chemistry 78 12639958
1991 Topographically designed analogues of [D-Pen,D-Pen5]enkephalin. Journal of medicinal chemistry 68 1648137
2016 Identification of GPR83 as the receptor for the neuroendocrine peptide PEN. Science signaling 67 27117253
2004 Pen-2 is sequestered in the endoplasmic reticulum and subjected to ubiquitylation and proteasome-mediated degradation in the absence of presenilin. The Journal of biological chemistry 67 14724271
2002 A new, potent urotensin II receptor peptide agonist containing a Pen residue at the disulfide bridge. Journal of medicinal chemistry 66 12238917
2000 The SAAS granin exhibits structural and functional homology to 7B2 and contains a highly potent hexapeptide inhibitor of PC1. FEBS letters 64 10812060
1994 Development of a model for the delta opioid receptor pharmacophore. 2. Conformationally restricted Phe3 replacements in the cyclic delta receptor selective tetrapeptide Tyr-c[D-Cys-Phe-D-Pen]OH (JOM-13). Journal of medicinal chemistry 62 7996550
2005 Ubiquilin regulates presenilin endoproteolysis and modulates gamma-secretase components, Pen-2 and nicastrin. The Biochemical journal 61 15975090
2004 Functional reconstitution of gamma-secretase through coordinated expression of presenilin, nicastrin, Aph-1, and Pen-2. Journal of neuroscience research 54 15248287
1999 Inhibition of allergen-induced pulmonary responses by the selective tryptase inhibitor 1,5-bis-[4-[(3-carbamimidoyl-benzenesulfonylamino)-methyl]-phenoxy]-pen tane (AMG-126737). Biochemical pharmacology 54 10591155
1997 Characterization of recombinant shrimp allergen Pen a 1 (tropomyosin). International archives of allergy and immunology 54 9130534
2011 ProSAAS-derived peptides are colocalized with neuropeptide Y and function as neuropeptides in the regulation of food intake. PloS one 53 22164236
2004 Both the sequence and length of the C terminus of PEN-2 are critical for intermolecular interactions and function of presenilin complexes. The Journal of biological chemistry 53 15322109
2022 Neoadjuvant Pembrolizumab and Chemotherapy in Resectable Esophageal Cancer: An Open-Label, Single-Arm Study (PEN-ICE). Frontiers in immunology 52 35720388
2011 The protease allergen Pen c 13 induces allergic airway inflammation and changes in epithelial barrier integrity and function in a murine model. The Journal of biological chemistry 51 21613216
2015 17β-Estradiol increases persistent Na(+) current and excitability of AVPV/PeN Kiss1 neurons in female mice. Molecular endocrinology (Baltimore, Md.) 49 25734516
2001 Inhibitory specificity and potency of proSAAS-derived peptides toward proprotein convertase 1. The Journal of biological chemistry 48 11435430
2000 ProSAAS processing in mouse brain and pituitary. The Journal of biological chemistry 47 11094058
2006 Protein nanoarray on Prolinker surface constructed by atomic force microscopy dip-pen nanolithography for analysis of protein interaction. Proteomics 44 16429461
2013 Interdigitated multicolored bioink micropatterns by multiplexed polymer pen lithography. Small (Weinheim an der Bergstrasse, Germany) 43 23554307
2013 A novel function for proSAAS as an amyloid anti-aggregant in Alzheimer's disease. Journal of neurochemistry 43 24102330
2006 Structural, immunological and functional properties of natural recombinant Pen a 1, the major allergen of Brown Shrimp, Penaeus aztecus. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 43 16630158
2001 Tissue distribution and processing of proSAAS by proprotein convertases. Journal of neurochemistry 43 11259501
2019 Discovery of an SSTR2-Targeting Maytansinoid Conjugate (PEN-221) with Potent Activity in Vitro and in Vivo. Journal of medicinal chemistry 42 30735385
2016 The neural chaperone proSAAS blocks α-synuclein fibrillation and neurotoxicity. Proceedings of the National Academy of Sciences of the United States of America 42 27457957
2019 Tracking a mass mortality outbreak of pen shell Pinna nobilis populations: A collaborative effort of scientists and citizens. Scientific reports 39 31527825
2010 The propeptide precursor proSAAS is involved in fetal neuropeptide processing and body weight regulation. Journal of neurochemistry 39 20367757
2002 Processing of proSAAS in neuroendocrine cell lines. The Biochemical journal 39 11742530
2001 Distribution of proSAAS-derived peptides in rat neuroendocrine tissues. Neuroscience 39 11672612
2001 Functional characterization of ProSAAS: similarities and differences with 7B2. The Journal of biological chemistry 39 11719503
2011 Functional and topological analysis of Pen-2, the fourth subunit of the gamma-secretase complex. The Journal of biological chemistry 38 21296884
2004 Presenilin modulates Pen-2 levels posttranslationally by protecting it from proteasomal degradation. Biochemistry 36 15035625
2019 Assessing patient PREFERence between the dulaglutide pen and the semaglutide pen: A crossover study (PREFER). Diabetes, obesity & metabolism 35 31646727
2013 Ferritin light chain interacts with PEN-2 and affects γ-secretase activity. Neuroscience letters 35 23685131
2017 Polymer-Pen Chemical Lift-Off Lithography. Nano letters 34 28409640
2013 Clinical and economic outcomes among patients with diabetes mellitus initiating insulin glargine pen versus vial. Postgraduate medicine 34 23748521
2006 Transcriptional regulation of PEN-2, a key component of the gamma-secretase complex, by CREB. Molecular and cellular biology 34 16449647
2010 Circadian integration of glutamatergic signals by little SAAS in novel suprachiasmatic circuits. PloS one 33 20830308
2015 SAAS-CNV: A Joint Segmentation Approach on Aggregated and Allele Specific Signals for the Identification of Somatic Copy Number Alterations with Next-Generation Sequencing Data. PLoS computational biology 30 26583378
2013 Blockade of islet amyloid polypeptide fibrillation and cytotoxicity by the secretory chaperones 7B2 and proSAAS. FEBS letters 30 24042052
2001 Coexpression of proprotein convertase SPC3 and the neuroendocrine precursor proSAAS. Endocrinology 29 11517193
2013 Probability of detecting Porcine reproductive and respiratory syndrome virus infection using pen-based swine oral fluid specimens as a function of within-pen prevalence. Journal of veterinary diagnostic investigation : official publication of the American Association of Veterinary Laboratory Diagnosticians, Inc 27 23536612
2003 A picoliter 'fountain-pen' using co-axial dual pipettes. Journal of neuroscience methods 27 12865150
2017 Anti-inflammatory effect of Man-Pen-Fang, a Chinese herbal compound, on chronic pelvic inflammation in rats. Journal of ethnopharmacology 26 28652014
2000 Complementary DNA cloning and immunologic characterization of a new Penicillium citrinum allergen (Pen c 3). The Journal of allergy and clinical immunology 26 10756236
2007 p53-Dependent Aph-1 and Pen-2 anti-apoptotic phenotype requires the integrity of the gamma-secretase complex but is independent of its activity. The Journal of biological chemistry 25 17276981
2004 Prohormone convertase 1 (PC1) processing and sorting: effect of PC1 propeptide and proSAAS. The Journal of endocrinology 25 15283695
2014 Pen-2 is essential for γ-secretase complex stability and trafficking but partially dispensable for endoproteolysis. Biochemistry 24 24941111
2003 An N-terminal fragment of ProSAAS (a granin-like neuroendocrine peptide precursor) is associated with tau inclusions in Pick's disease. Biochemical and biophysical research communications 24 12914799
2002 ProSAAS and prohormone convertase 1 are broadly expressed during mouse development. Brain research. Gene expression patterns 24 15018810
1999 Identification and expression of Pen c 2, a novel allergen from Penicillium citrinum. The Biochemical journal 24 10377244
2017 Antioxidant and functional properties of protein hydrolysates obtained from squid pen chitosan extraction effluent. Food chemistry 22 28274422
2015 Chitinolytic Bacteria-Assisted Conversion of Squid Pen and Its Effect on Dyes and Pigments Adsorption. Marine drugs 22 26213948
2019 Ultrafine and carboxylated β-chitin nanofibers prepared from squid pen and its transparent hydrogels. Carbohydrate polymers 21 30824071
2017 Clickable Antifouling Polymer Brushes for Polymer Pen Lithography. ACS applied materials & interfaces 21 28296390
2014 Pen and Pal are nucleotide-sugar dehydratases that convert UDP-GlcNAc to UDP-6-deoxy-D-GlcNAc-5,6-ene and then to UDP-4-keto-6-deoxy-L-AltNAc for CMP-pseudaminic acid synthesis in Bacillus thuringiensis. The Journal of biological chemistry 21 25414257
2010 Protein immobilization on Ni(II) ion patterns prepared by microcontact printing and dip-pen nanolithography. ACS nano 21 20104881
2005 Characterization of the reconstituted gamma-secretase complex from Sf9 cells co-expressing presenilin 1, nicastrin [correction of nacastrin], aph-1a, and pen-2. Biochemistry 21 15766275
2000 Tetrapeptide derivatives of [D-Pen(2),D-Pen(5)]-enkephalin (DPDPE) lacking an N-terminal tyrosine residue are agonists at the mu-opioid receptor. The Journal of pharmacology and experimental therapeutics 21 11082429
2012 Identification of critical amino acids in an immunodominant IgE epitope of Pen c 13, a major allergen from Penicillium citrinum. PloS one 20 22506037
2012 Pax6 directly down-regulates Pcsk1n expression thereby regulating PC1/3 dependent proinsulin processing. PloS one 20 23056534
2015 Quantitative real-time polymerase chain reaction for detecting Mycoplasma hyosynoviae and Mycoplasma hyorhinis in pen-based oral, tonsillar, and nasal fluids. Journal of veterinary science 19 25643803
2008 Identification of proSAAS homologs in lower vertebrates: conservation of hydrophobic helices and convertase-inhibiting sequences. Endocrinology 19 18948394
2005 PEN-2 gene mutation in a familial Alzheimer's disease case. Journal of neurology 19 16170650
2000 Antinociceptive activity of [beta-methyl-2', 6'-dimethyltyrosine(1)]-substituted cyclic [D-Pen(2), D-Pen(5)]Enkephalin and [D-Ala(2),Asp(4)]Deltorphin analogs. The Journal of pharmacology and experimental therapeutics 19 10734164
2014 ProSAAS-derived peptides are differentially processed and sorted in mouse brain and AtT-20 cells. PloS one 18 25148519
2023 SaaS sRNA promotes Salmonella intestinal invasion via modulating MAPK inflammatory pathway. Gut microbes 17 37158502
2022 Training Mid-Level Providers to Treat Severe Non-Communicable Diseases in Neno, Malawi through PEN-Plus Strategies. Annals of global health 15 36062045
2019 Painful tumors of the skin: "CALM HOG FLED PEN AND GETS BACK". Clinical, cosmetic and investigational dermatology 15 30858718
2002 Molecular and immunological characterization and IgE epitope mapping of Pen n 18, a major allergen of Penicillium notatum. The Biochemical journal 15 11964171
2019 Conditional Inactivation of Pen-2 in the Developing Neocortex Leads to Rapid Switch of Apical Progenitors to Basal Progenitors. The Journal of neuroscience : the official journal of the Society for Neuroscience 14 30692224
2015 Propylthiouracil Attenuates Experimental Pulmonary Hypertension via Suppression of Pen-2, a Key Component of Gamma-Secretase. PloS one 14 26367462
2012 Pen-2 is dispensable for endoproteolysis of presenilin 1, and nicastrin-Aph subcomplex is important for both γ-secretase assembly and substrate recruitment. Journal of neurochemistry 14 22973949
2022 Addressing severe chronic NCDs across Africa: measuring demand for the Package of Essential Non-communicable Disease Interventions-Plus (PEN-Plus). Health policy and planning 13 34977932
2020 Increased expression and retention of the secretory chaperone proSAAS following cell stress. Cell stress & chaperones 13 32607937
2020 The association between dietary patterns and nutritional status in community-dwelling older adults-the PEN-3S study. European journal of clinical nutrition 13 32951012
2019 Neuropeptide PEN and Its Receptor GPR83: Distribution, Signaling, and Regulation. ACS chemical neuroscience 13 30726666
2019 Applications of CRISPR systems in respiratory health: Entering a new 'red pen' era in genome editing. Respirology (Carlton, Vic.) 13 30883991
2019 Immunosensing of breast cancer tumor protein CA 15-3 (carbohydrate antigen 15.3) using a novel nano-bioink: A new platform for screening of proteins in human biofluids by pen-on-paper technology. International journal of biological macromolecules 13 30940584
2017 ProSAAS-derived peptides are regulated by cocaine and are required for sensitization to the locomotor effects of cocaine. Journal of neurochemistry 13 28881029
2016 Allergen Valency, Dose, and FcεRI Occupancy Set Thresholds for Secretory Responses to Pen a 1 and Motivate Design of Hypoallergens. Journal of immunology (Baltimore, Md. : 1950) 13 28039304
2015 A Frameshift Mutation in PEN-2 Causes Familial Comedones Syndrome. Dermatology (Basel, Switzerland) 13 26044244
2015 Poly(-β-hydroxybutyrate) (PHB) depolymerase PHAZ Pen from Penicillium expansum: purification, characterization and kinetic studies. 3 Biotech 13 28324398
2005 Haemonchus contortus and Trichostrongylus colubriformis in pen-trials with Javanese thin tail sheep and Kacang cross Etawah goats. Veterinary parasitology 13 16310309
2022 The proSAAS Chaperone Provides Neuroprotection and Attenuates Transsynaptic α-Synuclein Spread in Rodent Models of Parkinson's Disease. Journal of Parkinson's disease 12 35527562
2020 Evaluating the usability and safety of the semaglutide single-dose pen-injectors through summative (human factors) usability testing. Journal of diabetes investigation 12 33034163