PCS1N_MOUSE
ID PCS1N_MOUSE Reviewed; 258 AA.
AC Q9QXV0; Q91W26;
DT 31-OCT-2006, integrated into UniProtKB/Swiss-Prot.
DT 31-OCT-2006, sequence version 2.
DT 03-AUG-2022, entry version 123.
DE RecName: Full=ProSAAS;
DE AltName: Full=IA-4;
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 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=PEN-20;
DE Contains:
DE RecName: Full=PEN-19;
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=BigLEN {ECO:0000303|PubMed:24043826};
DE AltName: Full=SAAS CT(25-40);
DE Flags: Precursor;
GN Name=Pcsk1n;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, PROTEOLYTIC PROCESSING (KEP; BIG
RP SAAS; LITTLE SAAS; PEN AND LITTLE LEN), TISSUE SPECIFICITY, SUBCELLULAR
RP LOCATION, AND IDENTIFICATION BY MASS SPECTROMETRY.
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].
RC STRAIN=FVB/N; TISSUE=Colon;
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 IDENTIFICATION OF PCSK1-INHIBITING HEXAPEPTIDE.
RX PubMed=9756897; DOI=10.1074/jbc.273.41.26589;
RA Apletalina E., Appel J., Lamango N.S., Houghten R.A., Lindberg I.;
RT "Identification of inhibitors of prohormone convertases 1 and 2 using a
RT peptide combinatorial library.";
RL J. Biol. Chem. 273:26589-26595(1998).
RN [4]
RP TISSUE SPECIFICITY.
RX PubMed=9630436; DOI=10.1159/000054314;
RA Donadel G., Marinos N., DeSilva M.G., Lu J., Notkins A.L., Lan M.S.;
RT "Molecular cloning and characterization of a highly basic protein, IA-4,
RT expressed in pancreatic islets and brain.";
RL Neuroendocrinology 67:190-196(1998).
RN [5]
RP PROTEOLYTIC PROCESSING (LITTLE SAAS; PEN AND BIG LEN).
RX PubMed=11094058; DOI=10.1074/jbc.m009067200;
RA Mzhavia N., Berman Y., Che F.-Y., Fricker L.D., Devi L.A.;
RT "ProSAAS processing in mouse brain and pituitary.";
RL J. Biol. Chem. 276:6207-6213(2001).
RN [6]
RP TISSUE SPECIFICITY, AND PROTEOLYTIC PROCESSING.
RX PubMed=11259501; DOI=10.1046/j.1471-4159.2001.00165.x;
RA Sayah M., Fortenberry Y., Cameron A., Lindberg I.;
RT "Tissue distribution and processing of proSAAS by proprotein convertases.";
RL J. Neurochem. 76:1833-1841(2001).
RN [7]
RP FUNCTION, PROTEOLYTIC PROCESSING (BIG SAAS; LITTLE SAAS; BIG PEN-LEN; PEN;
RP PEN-20; PEN-19 AND BIG LEN), AND SUBCELLULAR LOCATION.
RX PubMed=11742530; DOI=10.1042/0264-6021:3610067;
RA Mzhavia N., Qian Y., Feng Y., Che F.-Y., Devi L.A., Fricker L.D.;
RT "Processing of proSAAS in neuroendocrine cell lines.";
RL Biochem. J. 361:67-76(2002).
RN [8]
RP DEVELOPMENTAL STAGE.
RX PubMed=15018810; DOI=10.1016/s1567-133x(02)00002-9;
RA Feng Y., Reznik S.E., Fricker L.D.;
RT "ProSAAS and prohormone convertase 1 are broadly expressed during mouse
RT development.";
RL Gene Expr. Patterns 1:135-140(2002).
RN [9]
RP FUNCTION, PROTEOLYTIC PROCESSING (BIG PEN-LEN AND BIG LEN), AND MUTAGENESIS
RP OF 241-LYS-ARG-242.
RX PubMed=11719503; DOI=10.1074/jbc.m104531200;
RA Fortenberry Y., Hwang J.R., Apletalina E.V., Lindberg I.;
RT "Functional characterization of ProSAAS: similarities and differences with
RT 7B2.";
RL J. Biol. Chem. 277:5175-5186(2002).
RN [10]
RP TISSUE SPECIFICITY (PEN).
RX PubMed=16631141; DOI=10.1016/j.brainres.2006.02.124;
RA Chakraborty T.R., Tkalych O., Nanno D., Garcia A.L., Devi L.A.,
RA Salton S.R.;
RT "Quantification of VGF- and pro-SAAS-derived peptides in endocrine tissues
RT and the brain, and their regulation by diet and cold stress.";
RL Brain Res. 1089:21-32(2006).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [12]
RP FUNCTION (BIG LEN).
RX PubMed=24043826; DOI=10.1073/pnas.1312938110;
RA Gomes I., Aryal D.K., Wardman J.H., Gupta A., Gagnidze K., Rodriguiz R.M.,
RA Kumar S., Wetsel W.C., Pintar J.E., Fricker L.D., Devi L.A.;
RT "GPR171 is a hypothalamic G protein-coupled receptor for BigLEN, a
RT neuropeptide involved in feeding.";
RL Proc. Natl. Acad. Sci. U.S.A. 110:16211-16216(2013).
RN [13]
RP FUNCTION (PEN).
RX PubMed=27117253; DOI=10.1126/scisignal.aad0694;
RA Gomes I., Bobeck E.N., Margolis E.B., Gupta A., Sierra S., Fakira A.K.,
RA Fujita W., Mueller T.D., Mueller A., Tschoep M.H., Kleinau G.,
RA Fricker L.D., Devi L.A.;
RT "Identification of GPR83 as the receptor for the neuroendocrine peptide
RT PEN.";
RL Sci. Signal. 9:ra43-ra43(2016).
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 processed peptides reduce PCSK1 activity in the endoplasmic
CC reticulum and Golgi. It reduces the activity of the 87 kDa form but not
CC the autocatalytically derived 66 kDa form of PCSK1. Subsequent
CC processing of proSAAS may eliminate the inhibition. Slows down
CC convertase-mediated processing of proopiomelanocortin and
CC proenkephalin. May control the intracellular timing of PCSK1 rather
CC than its total level of activity. {ECO:0000269|PubMed:10632593,
CC ECO:0000269|PubMed:11719503, ECO:0000269|PubMed:11742530}.
CC -!- FUNCTION: [Big LEN]: Endogenous ligand for GPR171 (PubMed:24043826).
CC Neuropeptide involved in the regulation of feeding (PubMed:24043826).
CC {ECO:0000269|PubMed:24043826}.
CC -!- FUNCTION: [PEN]: Endogenous ligand for GPR171. Neuropeptide involved in
CC the regulation of feeding. {ECO:0000269|PubMed:27117253}.
CC -!- SUBUNIT: Interacts via the C-terminal inhibitory domain with PCSK1 66
CC kDa form. {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:10632593,
CC ECO:0000269|PubMed:11742530}. Golgi apparatus, trans-Golgi network
CC {ECO:0000269|PubMed:11742530}.
CC -!- TISSUE SPECIFICITY: Expressed in brain (mostly hypothalamus and
CC pituitary) and gut. Expressed in trigeminal ganglia and neuroendocrine
CC cell lines. {ECO:0000269|PubMed:10632593, ECO:0000269|PubMed:11259501,
CC ECO:0000269|PubMed:9630436}.
CC -!- TISSUE SPECIFICITY: [PEN]: Expressed in pancreas, spinal cord and brain
CC (most abundant in striatum, hippocampus, pons and medulla, and cortex)
CC (at protein level). {ECO:0000269|PubMed:16631141}.
CC -!- DEVELOPMENTAL STAGE: Broadly expressed from 9 dpc to 11 dpc, with some
CC enrichment in neural tube-derived tissues. By 15 dpc, the expression is
CC largely restricted to neuroendocrine tissues.
CC {ECO:0000269|PubMed:15018810}.
CC -!- DOMAIN: ProSAAS(1-180) increases secretion of enzymatically inactive
CC PCSK1.
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.
CC -!- DOMAIN: [Big LEN]: The four C-terminal amino acids of Big LEN are
CC sufficient to bind and activate GPR171. {ECO:0000269|PubMed:24043826}.
CC -!- PTM: Proteolytically cleaved in the Golgi. Little SAAS, PEN, PEN-20 and
CC Big LEN are the major processed peptides in proSAAS-overexpressing AtT-
CC 20 pituitary corticotropic cell line. {ECO:0000269|PubMed:10632593,
CC ECO:0000269|PubMed:11094058, ECO:0000269|PubMed:11259501,
CC ECO:0000269|PubMed:11719503, ECO:0000269|PubMed:11742530}.
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DR EMBL; AF181560; AAF22641.1; -; mRNA.
DR EMBL; BC012263; AAH12263.1; -; mRNA.
DR CCDS; CCDS29979.1; -.
DR RefSeq; NP_038920.2; NM_013892.3.
DR AlphaFoldDB; Q9QXV0; -.
DR SMR; Q9QXV0; -.
DR BioGRID; 205954; 4.
DR IntAct; Q9QXV0; 1.
DR STRING; 10090.ENSMUSP00000040342; -.
DR MEROPS; I49.001; -.
DR iPTMnet; Q9QXV0; -.
DR PhosphoSitePlus; Q9QXV0; -.
DR CPTAC; non-CPTAC-3477; -.
DR MaxQB; Q9QXV0; -.
DR PaxDb; Q9QXV0; -.
DR PeptideAtlas; Q9QXV0; -.
DR PRIDE; Q9QXV0; -.
DR ProteomicsDB; 287969; -.
DR Antibodypedia; 579; 95 antibodies from 19 providers.
DR DNASU; 30052; -.
DR Ensembl; ENSMUST00000041096; ENSMUSP00000040342; ENSMUSG00000039278.
DR GeneID; 30052; -.
DR KEGG; mmu:30052; -.
DR UCSC; uc009snf.2; mouse.
DR CTD; 27344; -.
DR MGI; MGI:1353431; Pcsk1n.
DR VEuPathDB; HostDB:ENSMUSG00000039278; -.
DR eggNOG; ENOG502RYS0; Eukaryota.
DR GeneTree; ENSGT00390000013488; -.
DR HOGENOM; CLU_100077_0_0_1; -.
DR InParanoid; Q9QXV0; -.
DR OMA; VWGAPRT; -.
DR OrthoDB; 1511698at2759; -.
DR PhylomeDB; Q9QXV0; -.
DR TreeFam; TF338201; -.
DR BioGRID-ORCS; 30052; 4 hits in 76 CRISPR screens.
DR PRO; PR:Q9QXV0; -.
DR Proteomes; UP000000589; Chromosome X.
DR RNAct; Q9QXV0; protein.
DR Bgee; ENSMUSG00000039278; Expressed in entorhinal cortex and 155 other tissues.
DR Genevisible; Q9QXV0; MM.
DR GO; GO:0005615; C:extracellular space; IDA:MGI.
DR GO; GO:0030141; C:secretory granule; IDA:MGI.
DR GO; GO:0005802; C:trans-Golgi network; IDA:MGI.
DR GO; GO:0004866; F:endopeptidase inhibitor activity; ISO:MGI.
DR GO; GO:0004867; F:serine-type endopeptidase inhibitor activity; IDA:MGI.
DR GO; GO:0007218; P:neuropeptide signaling pathway; IEA:UniProtKB-KW.
DR GO; GO:0016486; P:peptide hormone processing; IDA:MGI.
DR GO; GO:0009409; P:response to cold; IDA:MGI.
DR GO; GO:0002021; P:response to dietary excess; IDA:MGI.
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; Golgi apparatus; Neuropeptide;
KW Reference proteome; Secreted; Signal.
FT SIGNAL 1..33
FT /evidence="ECO:0000255"
FT CHAIN 34..258
FT /note="ProSAAS"
FT /id="PRO_0000259681"
FT PEPTIDE 34..59
FT /note="Big SAAS"
FT /id="PRO_0000259683"
FT PEPTIDE 34..40
FT /note="KEP"
FT /id="PRO_0000259682"
FT PEPTIDE 42..59
FT /note="Little SAAS"
FT /id="PRO_0000259684"
FT PEPTIDE 219..258
FT /note="Big PEN-LEN"
FT /id="PRO_0000259685"
FT PEPTIDE 219..240
FT /note="PEN"
FT /id="PRO_0000259686"
FT PEPTIDE 219..238
FT /note="PEN-20"
FT /id="PRO_0000259687"
FT PEPTIDE 219..237
FT /note="PEN-19"
FT /id="PRO_0000259688"
FT PEPTIDE 243..258
FT /note="Big LEN"
FT /id="PRO_0000259690"
FT PEPTIDE 243..252
FT /note="Little LEN"
FT /id="PRO_0000259689"
FT REGION 34..213
FT /note="ProSAAS(1-180)"
FT REGION 156..188
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 204..230
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 219..258
FT /note="C-terminal inhibitory domain; interacts with PCSK1"
FT REGION 239..258
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 237..242
FT /note="Sufficient for inhibition of PCSK1"
FT MUTAGEN 241..242
FT /note="KR->SS: Abolishes inhibition of PCSK1."
FT /evidence="ECO:0000269|PubMed:11719503"
FT CONFLICT 83
FT /note="L -> Q (in Ref. 1; AAF22641)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 258 AA; 27270 MW; 4197C8B077A20A22 CRC64;
MAGSPLLCGP RAGGVGILVL LLLGLLRLPP TLSARPVKEP RSLSAASAPL VETSTPLRLR
RAVPRGEAAG AVQELARALA HLLEAERQER ARAEAQEAED QQARVLAQLL RAWGSPRASD
PPLAPDDDPD APAAQLARAL LRARLDPAAL AAQLVPAPAA APRPRPPVYD DGPTGPDVED
AGDETPDVDP ELLRYLLGRI LTGSSEPEAA PAPRRLRRSV DQDLGPEVPP ENVLGALLRV
KRLENPSPQA PARRLLPP
