PCS1N_HUMAN
ID PCS1N_HUMAN Reviewed; 260 AA.
AC Q9UHG2; Q4VC04;
DT 31-OCT-2006, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-2000, sequence version 1.
DT 03-AUG-2022, entry version 149.
DE RecName: Full=ProSAAS;
DE AltName: Full=Proprotein convertase subtilisin/kexin type 1 inhibitor;
DE Short=Proprotein convertase 1 inhibitor;
DE AltName: Full=pro-SAAS;
DE Contains:
DE RecName: Full=KEP;
DE Contains:
DE RecName: Full=Big SAAS;
DE Short=b-SAAS;
DE Contains:
DE RecName: Full=Little SAAS;
DE Short=l-SAAS;
DE AltName: Full=N-proSAAS;
DE Contains:
DE RecName: Full=Big PEN-LEN;
DE Short=b-PEN-LEN;
DE AltName: Full=SAAS CT(1-49);
DE Contains:
DE RecName: Full=PEN;
DE Contains:
DE RecName: Full=Little LEN;
DE Short=l-LEN;
DE Contains:
DE RecName: Full=Big LEN;
DE Short=b-LEN;
DE AltName: Full=SAAS CT(25-40);
DE Flags: Precursor;
GN Name=PCSK1N;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RX PubMed=10632593; DOI=10.1523/jneurosci.20-02-00639.2000;
RA Fricker L., McKinzie A.A., Sun J., Curran E., Qian Y., Yan L.,
RA Patterson S.D., Courchesne P.L., Richards B., Levin N., Mzhavia N.,
RA Devi L.A., Douglass J.;
RT "Identification and characterization of proSAAS, a granin-like
RT neuroendocrine peptide precursor that inhibits prohormone processing.";
RL J. Neurosci. 20:639-648(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT THR-31.
RC TISSUE=Brain, and Uterus;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP MUTAGENESIS OF VAL-235; LEU-236; GLY-237; LEU-240; ARG-241; VAL-242;
RP LYS-243; ARG-244; LEU-245 AND GLU-246.
RX PubMed=11435430; DOI=10.1074/jbc.m104064200;
RA Basak A., Koch P., Dupelle M., Fricker L.D., Devi L.A., Chretien M.,
RA Seidah N.G.;
RT "Inhibitory specificity and potency of proSAAS-derived peptides toward
RT proprotein convertase 1.";
RL J. Biol. Chem. 276:32720-32728(2001).
RN [4]
RP SUBCELLULAR LOCATION (PROTEIN TAU DEPOSITS), AND PROTEOLYTIC PROCESSING.
RX PubMed=12914799; DOI=10.1016/s0006-291x(03)01391-3;
RA Kikuchi K., Arawaka S., Koyama S., Kimura H., Ren C.H., Wada M.,
RA Kawanami T., Kurita K., Daimon M., Kawakatsu S., Kadoya T., Goto K.,
RA Kato T.;
RT "An N-terminal fragment of ProSAAS (a granin-like neuroendocrine peptide
RT precursor) is associated with tau inclusions in Pick's disease.";
RL Biochem. Biophys. Res. Commun. 308:646-654(2003).
RN [5]
RP SUBCELLULAR LOCATION (PROTEIN TAU DEPOSITS).
RX PubMed=14746899; DOI=10.1016/j.neulet.2003.11.028;
RA Wada M., Ren C.H., Koyama S., Arawaka S., Kawakatsu S., Kimura H.,
RA Nagasawa H., Kawanami T., Kurita K., Daimon M., Hirano A., Kato T.;
RT "A human granin-like neuroendocrine peptide precursor (proSAAS)
RT immunoreactivity in tau inclusions of Alzheimer's disease and parkinsonism-
RT dementia complex on Guam.";
RL Neurosci. Lett. 356:49-52(2004).
RN [6]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT THR-53 AND THR-247, AND STRUCTURE
RP OF CARBOHYDRATES.
RC TISSUE=Cerebrospinal fluid;
RX PubMed=19838169; DOI=10.1038/nmeth.1392;
RA Nilsson J., Rueetschi U., Halim A., Hesse C., Carlsohn E., Brinkmalm G.,
RA Larson G.;
RT "Enrichment of glycopeptides for glycan structure and attachment site
RT identification.";
RL Nat. Methods 6:809-811(2009).
RN [7]
RP GLYCOSYLATION AT THR-53; SER-228 AND THR-247, STRUCTURE OF CARBOHYDRATES,
RP AND IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=22171320; DOI=10.1074/mcp.m111.013649;
RA Halim A., Nilsson J., Ruetschi U., Hesse C., Larson G.;
RT "Human urinary glycoproteomics; attachment site specific analysis of N- and
RT O-linked glycosylations by CID and ECD.";
RL Mol. Cell. Proteomics 11:1-17(2012).
RN [8]
RP GLYCOSYLATION AT SER-228, AND IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=23234360; DOI=10.1021/pr300963h;
RA Halim A., Ruetschi U., Larson G., Nilsson J.;
RT "LC-MS/MS characterization of O-glycosylation sites and glycan structures
RT of human cerebrospinal fluid glycoproteins.";
RL J. Proteome Res. 12:573-584(2013).
CC -!- FUNCTION: May function in the control of the neuroendocrine secretory
CC pathway. Proposed be a specific endogenous inhibitor of PCSK1. ProSAAS
CC and Big PEN-LEN, both containing the C-terminal inhibitory domain, but
CC not the further processed peptides reduce PCSK1 activity in the
CC endoplasmic reticulum and Golgi. It reduces the activity of the 84 kDa
CC form but not the autocatalytically derived 66 kDa form of PCSK1.
CC Subsequent processing of proSAAS may eliminate the inhibition. Slows
CC down convertase-mediated processing of proopiomelanocortin and
CC proenkephalin. May control the intracellular timing of PCSK1 rather
CC than its total level of activity (By similarity).
CC {ECO:0000250|UniProtKB:Q9QXV0}.
CC -!- FUNCTION: [Big LEN]: Endogenous ligand for GPR171. Neuropeptide
CC involved in the regulation of feeding. {ECO:0000250|UniProtKB:Q9QXV0}.
CC -!- FUNCTION: [PEN]: Endogenous ligand for GPR171. Neuropeptide involved in
CC the regulation of feeding. {ECO:0000250|UniProtKB:Q9QXV0}.
CC -!- SUBUNIT: Interacts via the C-terminal inhibitory domain with PCSK1 66
CC kDa form. {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250|UniProtKB:Q9QXV0}. Golgi
CC apparatus, trans-Golgi network {ECO:0000250|UniProtKB:Q9QXV0}. Note=A
CC N-terminal processed peptide, probably Big SAAS or Little SAAS, is
CC accumulated in cytoplasmic protein tau deposits in frontotemporal
CC dementia and parkinsonism linked to chromosome 17 (Pick disease),
CC Alzheimer disease and amyotrophic lateral sclerosis-
CC parkinsonism/dementia complex 1 (Guam disease).
CC {ECO:0000269|PubMed:12914799, ECO:0000269|PubMed:14746899}.
CC -!- TISSUE SPECIFICITY: Expressed in brain and pancreas.
CC {ECO:0000269|PubMed:10632593}.
CC -!- DOMAIN: ProSAAS(1-180) increases secretion of enzymatically inactive
CC PCSK1. {ECO:0000250}.
CC -!- DOMAIN: The C-terminal inhibitory domain is involved in inhibition of
CC PCSK1. It corresponds to the probable processing intermediate Big PEN-
CC LEN, binds to PCSK1 in vitro and contains the hexapeptide L-L-R-V-K-R,
CC which, as a synthetic peptide, is sufficient for PCSK1 inhibition (By
CC similarity). {ECO:0000250}.
CC -!- DOMAIN: [Big LEN]: The four C-terminal amino acids of Big LEN are
CC sufficient to bind and activate GPR171. {ECO:0000250|UniProtKB:Q9QXV0}.
CC -!- PTM: Proteolytically cleaved in the Golgi.
CC {ECO:0000269|PubMed:12914799}.
CC -!- PTM: O-glycosylated with a core 1 or possibly core 8 glycan.
CC {ECO:0000269|PubMed:19838169, ECO:0000269|PubMed:22171320,
CC ECO:0000269|PubMed:23234360}.
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DR EMBL; AF181562; AAF22643.1; -; mRNA.
DR EMBL; BC002851; AAH02851.1; -; mRNA.
DR CCDS; CCDS14307.1; -.
DR RefSeq; NP_037403.1; NM_013271.4.
DR AlphaFoldDB; Q9UHG2; -.
DR SMR; Q9UHG2; -.
DR BioGRID; 118156; 15.
DR IntAct; Q9UHG2; 7.
DR MINT; Q9UHG2; -.
DR STRING; 9606.ENSP00000218230; -.
DR MEROPS; I49.001; -.
DR GlyConnect; 743; 1 O-Linked glycan (3 sites).
DR GlyGen; Q9UHG2; 3 sites, 2 O-linked glycans (3 sites).
DR iPTMnet; Q9UHG2; -.
DR PhosphoSitePlus; Q9UHG2; -.
DR BioMuta; PCSK1N; -.
DR DMDM; 74735013; -.
DR jPOST; Q9UHG2; -.
DR MassIVE; Q9UHG2; -.
DR MaxQB; Q9UHG2; -.
DR PaxDb; Q9UHG2; -.
DR PeptideAtlas; Q9UHG2; -.
DR PRIDE; Q9UHG2; -.
DR ProteomicsDB; 84349; -.
DR Antibodypedia; 579; 95 antibodies from 19 providers.
DR DNASU; 27344; -.
DR Ensembl; ENST00000218230.6; ENSP00000218230.5; ENSG00000102109.9.
DR GeneID; 27344; -.
DR KEGG; hsa:27344; -.
DR MANE-Select; ENST00000218230.6; ENSP00000218230.5; NM_013271.5; NP_037403.1.
DR UCSC; uc004dkz.6; human.
DR CTD; 27344; -.
DR DisGeNET; 27344; -.
DR GeneCards; PCSK1N; -.
DR HGNC; HGNC:17301; PCSK1N.
DR HPA; ENSG00000102109; Group enriched (brain, pituitary gland).
DR MIM; 300399; gene.
DR neXtProt; NX_Q9UHG2; -.
DR OpenTargets; ENSG00000102109; -.
DR PharmGKB; PA33090; -.
DR VEuPathDB; HostDB:ENSG00000102109; -.
DR eggNOG; ENOG502RYS0; Eukaryota.
DR GeneTree; ENSGT00390000013488; -.
DR HOGENOM; CLU_100077_0_0_1; -.
DR InParanoid; Q9UHG2; -.
DR OMA; VWGAPRT; -.
DR OrthoDB; 1511698at2759; -.
DR PhylomeDB; Q9UHG2; -.
DR TreeFam; TF338201; -.
DR PathwayCommons; Q9UHG2; -.
DR SignaLink; Q9UHG2; -.
DR BioGRID-ORCS; 27344; 8 hits in 691 CRISPR screens.
DR GenomeRNAi; 27344; -.
DR Pharos; Q9UHG2; Tbio.
DR PRO; PR:Q9UHG2; -.
DR Proteomes; UP000005640; Chromosome X.
DR RNAct; Q9UHG2; protein.
DR Bgee; ENSG00000102109; Expressed in adenohypophysis and 137 other tissues.
DR Genevisible; Q9UHG2; HS.
DR GO; GO:0005615; C:extracellular space; IBA:GO_Central.
DR GO; GO:0030141; C:secretory granule; IEA:Ensembl.
DR GO; GO:0005802; C:trans-Golgi network; IEA:Ensembl.
DR GO; GO:0004866; F:endopeptidase inhibitor activity; IBA:GO_Central.
DR GO; GO:0004867; F:serine-type endopeptidase inhibitor activity; IEA:Ensembl.
DR GO; GO:0005102; F:signaling receptor binding; TAS:ProtInc.
DR GO; GO:0007218; P:neuropeptide signaling pathway; IEA:UniProtKB-KW.
DR GO; GO:0016486; P:peptide hormone processing; IEA:Ensembl.
DR GO; GO:0009409; P:response to cold; IEA:Ensembl.
DR GO; GO:0002021; P:response to dietary excess; IEA:Ensembl.
DR InterPro; IPR010832; ProSAAS.
DR PANTHER; PTHR15531; PTHR15531; 1.
DR Pfam; PF07259; ProSAAS; 1.
PE 1: Evidence at protein level;
KW Cleavage on pair of basic residues; Glycoprotein; Golgi apparatus;
KW Neuropeptide; Reference proteome; Secreted; Signal.
FT SIGNAL 1..33
FT /evidence="ECO:0000255"
FT CHAIN 34..260
FT /note="ProSAAS"
FT /id="PRO_0000259673"
FT PEPTIDE 34..59
FT /note="Big SAAS"
FT /evidence="ECO:0000250"
FT /id="PRO_0000259675"
FT PEPTIDE 34..40
FT /note="KEP"
FT /evidence="ECO:0000250"
FT /id="PRO_0000259674"
FT PEPTIDE 42..59
FT /note="Little SAAS"
FT /evidence="ECO:0000250"
FT /id="PRO_0000259676"
FT PEPTIDE 221..260
FT /note="Big PEN-LEN"
FT /evidence="ECO:0000250"
FT /id="PRO_0000259677"
FT PEPTIDE 221..242
FT /note="PEN"
FT /evidence="ECO:0000250"
FT /id="PRO_0000259678"
FT PEPTIDE 245..260
FT /note="Big LEN"
FT /evidence="ECO:0000250"
FT /id="PRO_0000259679"
FT PEPTIDE 245..254
FT /note="Little LEN"
FT /evidence="ECO:0000250"
FT /id="PRO_0000259680"
FT REGION 34..215
FT /note="ProSAAS(1-180)"
FT /evidence="ECO:0000250"
FT REGION 165..188
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 221..260
FT /note="C-terminal inhibitory domain; interacts with PCSK1"
FT /evidence="ECO:0000250"
FT MOTIF 239..244
FT /note="Sufficient for inhibition of PCSK1"
FT CARBOHYD 53
FT /note="O-linked (GalNAc...) threonine"
FT /evidence="ECO:0000269|PubMed:19838169,
FT ECO:0000269|PubMed:22171320"
FT CARBOHYD 228
FT /note="O-linked (GalNAc...) serine"
FT /evidence="ECO:0000269|PubMed:22171320,
FT ECO:0000269|PubMed:23234360"
FT CARBOHYD 247
FT /note="O-linked (GalNAc...) threonine"
FT /evidence="ECO:0000269|PubMed:19838169,
FT ECO:0000269|PubMed:22171320"
FT VARIANT 31
FT /note="A -> T (in dbSNP:rs11538176)"
FT /evidence="ECO:0000269|PubMed:15489334"
FT /id="VAR_028971"
FT MUTAGEN 235
FT /note="V->A: Reduces inhibition of PCSK1."
FT /evidence="ECO:0000269|PubMed:11435430"
FT MUTAGEN 236
FT /note="L->A: Greatly reduces inhibition of PCSK1."
FT /evidence="ECO:0000269|PubMed:11435430"
FT MUTAGEN 237
FT /note="G->A: Reduces inhibition of PCSK1."
FT /evidence="ECO:0000269|PubMed:11435430"
FT MUTAGEN 240
FT /note="L->A: Reduces inhibition of PCSK1."
FT /evidence="ECO:0000269|PubMed:11435430"
FT MUTAGEN 241
FT /note="R->A: Reduces inhibition of PCSK1."
FT /evidence="ECO:0000269|PubMed:11435430"
FT MUTAGEN 242
FT /note="V->A: Reduces inhibition of PCSK1."
FT /evidence="ECO:0000269|PubMed:11435430"
FT MUTAGEN 243
FT /note="K->A: Abolishes inhibition of PCSK1."
FT /evidence="ECO:0000269|PubMed:11435430"
FT MUTAGEN 244
FT /note="R->A: Abolishes inhibition of PCSK1."
FT /evidence="ECO:0000269|PubMed:11435430"
FT MUTAGEN 245
FT /note="L->A: Reduces inhibition of PCSK1."
FT /evidence="ECO:0000269|PubMed:11435430"
FT MUTAGEN 246
FT /note="E->A: Reduces inhibition of PCSK1."
FT /evidence="ECO:0000269|PubMed:11435430"
SQ SEQUENCE 260 AA; 27372 MW; FF8E2722784B7A5C CRC64;
MAGSPLLWGP RAGGVGLLVL LLLGLFRPPP ALCARPVKEP RGLSAASPPL AETGAPRRFR
RSVPRGEAAG AVQELARALA HLLEAERQER ARAEAQEAED QQARVLAQLL RVWGAPRNSD
PALGLDDDPD APAAQLARAL LRARLDPAAL AAQLVPAPVP AAALRPRPPV YDDGPAGPDA
EEAGDETPDV DPELLRYLLG RILAGSADSE GVAAPRRLRR AADHDVGSEL PPEGVLGALL
RVKRLETPAP QVPARRLLPP
