ID   SPCS3_HUMAN             Reviewed;         180 AA.
AC   P61009; P12280; Q9H0S7;
DT   26-APR-2004, integrated into UniProtKB/Swiss-Prot.
DT   26-APR-2004, sequence version 1.
DT   10-JUN-2026, entry version 173.
DE   RecName: Full=Signal peptidase complex subunit 3;
DE   AltName: Full=Microsomal signal peptidase 22/23 kDa subunit;
DE            Short=SPC22/23;
DE            Short=SPase 22/23 kDa subunit;
GN   Name=SPCS3; Synonyms=SPC22; ORFNames=UNQ1841/PRO3567;
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 [LARGE SCALE MRNA].
RC   TISSUE=Brain;
RX   PubMed=11230166; DOI=10.1101/gr.gr1547r;
RA   Wiemann S., Weil B., Wellenreuther R., Gassenhuber J., Glassl S.,
RA   Ansorge W., Boecher M., Bloecker H., Bauersachs S., Blum H., Lauber J.,
RA   Duesterhoeft A., Beyer A., Koehrer K., Strack N., Mewes H.-W.,
RA   Ottenwaelder B., Obermaier B., Tampe J., Heubner D., Wambutt R., Korn B.,
RA   Klein M., Poustka A.;
RT   "Towards a catalog of human genes and proteins: sequencing and analysis of
RT   500 novel complete protein coding human cDNAs.";
RL   Genome Res. 11:422-435(2001).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Small intestine;
RX   PubMed=14702039; DOI=10.1038/ng1285;
RA   Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA   Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA   Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA   Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA   Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA   Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA   Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA   Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA   Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA   Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA   Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA   Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA   Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA   Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA   Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA   Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA   Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA   Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA   Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA   Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA   Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA   Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA   Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA   Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA   Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA   Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA   Isogai T., Sugano S.;
RT   "Complete sequencing and characterization of 21,243 full-length human
RT   cDNAs.";
RL   Nat. Genet. 36:40-45(2004).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX   PubMed=12975309; DOI=10.1101/gr.1293003;
RA   Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA   Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA   Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A.,
RA   Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D.,
RA   Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L.,
RA   Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C.,
RA   Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J.,
RA   Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.;
RT   "The secreted protein discovery initiative (SPDI), a large-scale effort to
RT   identify novel human secreted and transmembrane proteins: a bioinformatics
RT   assessment.";
RL   Genome Res. 13:2265-2270(2003).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Pancreas;
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   [5]
RP   GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-141.
RC   TISSUE=Liver;
RX   PubMed=19159218; DOI=10.1021/pr8008012;
RA   Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT   "Glycoproteomics analysis of human liver tissue by combination of multiple
RT   enzyme digestion and hydrazide chemistry.";
RL   J. Proteome Res. 8:651-661(2009).
RN   [6]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA   Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA   Bennett K.L., Superti-Furga G., Colinge J.;
RT   "Initial characterization of the human central proteome.";
RL   BMC Syst. Biol. 5:17-17(2011).
RN   [7]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA   Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA   Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E.,
RA   Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT   "N-terminal acetylome analyses and functional insights of the N-terminal
RT   acetyltransferase NatB.";
RL   Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN   [8]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Liver;
RX   PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA   Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA   Ye M., Zou H.;
RT   "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT   phosphoproteome.";
RL   J. Proteomics 96:253-262(2014).
RN   [9]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=25944712; DOI=10.1002/pmic.201400617;
RA   Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA   Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT   "N-terminome analysis of the human mitochondrial proteome.";
RL   Proteomics 15:2519-2524(2015).
RN   [10]
RP   FUNCTION.
RX   PubMed=27499293; DOI=10.1016/j.molcel.2016.06.032;
RA   Chen Q., Denard B., Lee C.E., Han S., Ye J.S., Ye J.;
RT   "Inverting the topology of a transmembrane protein by regulating the
RT   translocation of the first transmembrane helix.";
RL   Mol. Cell 63:567-578(2016).
RN   [11]
RP   FUNCTION (MICROBIAL INFECTION).
RX   PubMed=27383988; DOI=10.1038/nature18625;
RA   Zhang R., Miner J.J., Gorman M.J., Rausch K., Ramage H., White J.P.,
RA   Zuiani A., Zhang P., Fernandez E., Zhang Q., Dowd K.A., Pierson T.C.,
RA   Cherry S., Diamond M.S.;
RT   "A CRISPR screen defines a signal peptide processing pathway required by
RT   flaviviruses.";
RL   Nature 535:164-168(2016).
RN   [12] {ECO:0007744|PDB:7P2P, ECO:0007744|PDB:7P2Q}
RP   STRUCTURE BY ELECTRON MICROSCOPY (4.9 ANGSTROMS), FUNCTION, IDENTIFICATION
RP   IN THE SIGNAL PEPTIDASE COMPLEX, AND GLYCOSYLATION AT ASN-141.
RX   PubMed=34388369; DOI=10.1016/j.molcel.2021.07.031;
RA   Liaci A.M., Steigenberger B., Telles de Souza P.C., Tamara S.,
RA   Groellers-Mulderij M., Ogrissek P., Marrink S.J., Scheltema R.A.,
RA   Foerster F.;
RT   "Structure of the human signal peptidase complex reveals the determinants
RT   for signal peptide cleavage.";
RL   Mol. Cell 81:3934-3948.e11(2021).
CC   -!- FUNCTION: Essential component of the signal peptidase complex (SPC)
CC       which catalyzes the cleavage of N-terminal signal sequences from
CC       nascent proteins as they are translocated into the lumen of the
CC       endoplasmic reticulum (PubMed:27499293, PubMed:34388369). Essential for
CC       the SPC catalytic activity, possibly by stabilizing and positioning the
CC       active center of the complex close to the lumenal surface (By
CC       similarity). {ECO:0000250|UniProtKB:Q12133,
CC       ECO:0000269|PubMed:27499293, ECO:0000269|PubMed:34388369}.
CC   -!- FUNCTION: (Microbial infection) Plays an important role in virion
CC       production of flaviviruses such as West Nile virus, Japanese
CC       enchephalitis virus, Dengue virus type 2 and Yellow Fever virus.
CC       {ECO:0000269|PubMed:27383988}.
CC   -!- SUBUNIT: Component of the signal peptidase complex paralog A (SPC-A)
CC       composed of a catalytic subunit SEC11A and three accessory subunits
CC       SPCS1, SPCS2 and SPCS3 (PubMed:34388369). Component of the signal
CC       peptidase complex paralog C (SPC-C) composed of a catalytic subunit
CC       SEC11C and three accessory subunits SPCS1, SPCS2 and SPCS3
CC       (PubMed:34388369). Within the complex, interacts with SEC11A or SEC11C
CC       and SPCS1 (PubMed:34388369). The complex induces a local thinning of
CC       the ER membrane which is used to measure the length of the signal
CC       peptide (SP) h-region of protein substrates (PubMed:34388369). This
CC       ensures the selectivity of the complex towards h-regions shorter than
CC       18-20 amino acids (PubMed:34388369). {ECO:0000269|PubMed:34388369}.
CC   -!- INTERACTION:
CC       P61009; P54253: ATXN1; NbExp=4; IntAct=EBI-6166040, EBI-930964;
CC       P61009; P42858: HTT; NbExp=6; IntAct=EBI-6166040, EBI-466029;
CC       P61009; P67812: SEC11A; NbExp=7; IntAct=EBI-6166040, EBI-1042500;
CC       P61009; Q9BY50: SEC11C; NbExp=8; IntAct=EBI-6166040, EBI-2855401;
CC   -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC       {ECO:0000250|UniProtKB:P61008}; Single-pass type II membrane protein
CC       {ECO:0000250|UniProtKB:P61008}.
CC   -!- SIMILARITY: Belongs to the SPCS3 family. {ECO:0000305}.
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DR   EMBL; AL136660; CAB66595.1; -; mRNA.
DR   EMBL; AK026302; BAB15437.1; -; mRNA.
DR   EMBL; AY359044; AAQ89403.1; -; mRNA.
DR   EMBL; BC047290; AAH47290.1; -; mRNA.
DR   CCDS; CCDS54823.1; -.
DR   RefSeq; NP_068747.1; NM_021928.4.
DR   PDB; 7P2P; EM; 4.90 A; B=1-180.
DR   PDB; 7P2Q; EM; 4.90 A; B=1-180.
DR   PDBsum; 7P2P; -.
DR   PDBsum; 7P2Q; -.
DR   AlphaFoldDB; P61009; -.
DR   EMDB; EMD-13171; -.
DR   EMDB; EMD-13172; -.
DR   SMR; P61009; -.
DR   BioGRID; 121940; 173.
DR   ComplexPortal; CPX-2847; Signal peptidase complex, SEC11A variant.
DR   ComplexPortal; CPX-7205; Signal peptidase complex, SEC11C variant.
DR   FunCoup; P61009; 1483.
DR   IntAct; P61009; 91.
DR   MINT; P61009; -.
DR   NDEx; IQUERY-CP-SPCS3; 5 NDEx IQuery Curated Pathways.
DR   STRING; 9606.ENSP00000427463; -.
DR   ChEMBL; CHEMBL6066491; -.
DR   GlyCosmos; P61009; 1 site, No reported glycans.
DR   GlyGen; P61009; 2 sites, 1 N-linked glycan (1 site), 1 O-linked glycan (1 site).
DR   iPTMnet; P61009; -.
DR   PhosphoSitePlus; P61009; -.
DR   SwissPalm; P61009; -.
DR   BioMuta; SPCS3; -.
DR   DMDM; 46577648; -.
DR   jPOST; P61009; -.
DR   MassIVE; P61009; -.
DR   PaxDb; 9606-ENSP00000427463; -.
DR   PeptideAtlas; P61009; -.
DR   ProteomicsDB; 57246; -.
DR   Pumba; P61009; -.
DR   TopDownProteomics; P61009; -.
DR   Antibodypedia; 28660; 69 antibodies from 21 providers.
DR   DNASU; 60559; -.
DR   Ensembl; ENST00000503362.2; ENSP00000427463.1; ENSG00000129128.13.
DR   GeneID; 60559; -.
DR   KEGG; hsa:60559; -.
DR   MANE-Select; ENST00000503362.2; ENSP00000427463.1; NM_021928.4; NP_068747.1.
DR   UCSC; uc003iur.5; human.
DR   AGR; HGNC:26212; -.
DR   ClinPGx; PA134910080; -.
DR   CTD; 60559; -.
DR   DisGeNET; 60559; -.
DR   GeneCards; SPCS3; -.
DR   HGNC; HGNC:26212; SPCS3.
DR   HPA; ENSG00000129128; Low tissue specificity.
DR   MIM; 618854; gene.
DR   OpenTargets; ENSG00000129128; -.
DR   VEuPathDB; HostDB:ENSG00000129128; -.
DR   eggNOG; KOG3372; Eukaryota.
DR   GeneTree; ENSGT00390000009223; -.
DR   HOGENOM; CLU_068714_1_0_1; -.
DR   InParanoid; P61009; -.
DR   OMA; FWDDGHG; -.
DR   OrthoDB; 10261524at2759; -.
DR   PAN-GO; P61009; 3 GO annotations based on evolutionary models.
DR   PhylomeDB; P61009; -.
DR   PathwayCommons; P61009; -.
DR   Reactome; R-HSA-1799339; SRP-dependent cotranslational protein targeting to membrane.
DR   Reactome; R-HSA-381771; Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1).
DR   Reactome; R-HSA-400511; Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP).
DR   Reactome; R-HSA-422085; Synthesis, secretion, and deacylation of Ghrelin.
DR   Reactome; R-HSA-9768727; Regulation of CDH1 posttranslational processing and trafficking to plasma membrane.
DR   Reactome; R-HSA-9828806; Maturation of hRSV A proteins.
DR   Reactome; R-HSA-9918432; Maturation of DENV proteins.
DR   SignaLink; P61009; -.
DR   Agora; ENSG00000129128; -.
DR   BioGRID-ORCS; 60559; 748 hits in 1165 CRISPR screens.
DR   ChiTaRS; SPCS3; human.
DR   GenomeRNAi; 60559; -.
DR   Pharos; P61009; Tbio.
DR   PRO; PR:P61009; -.
DR   Proteomes; UP000005640; Chromosome 4.
DR   RNAct; P61009; protein.
DR   Bgee; ENSG00000129128; Expressed in corpus epididymis and 212 other cell types or tissues.
DR   GO; GO:0005783; C:endoplasmic reticulum; IDA:LIFEdb.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:ComplexPortal.
DR   GO; GO:0005787; C:signal peptidase complex; IBA:GO_Central.
DR   GO; GO:0045047; P:protein targeting to ER; IBA:GO_Central.
DR   GO; GO:0006508; P:proteolysis; IDA:UniProtKB.
DR   GO; GO:0006465; P:signal peptide processing; IDA:ComplexPortal.
DR   GO; GO:0019082; P:viral protein processing; IMP:UniProtKB.
DR   InterPro; IPR007653; SPC3.
DR   PANTHER; PTHR12804; MICROSOMAL SIGNAL PEPTIDASE 23 KD SUBUNIT SPC22/23; 1.
DR   PANTHER; PTHR12804:SF0; SIGNAL PEPTIDASE COMPLEX SUBUNIT 3; 1.
DR   Pfam; PF04573; SPC22; 1.
DR   PIRSF; PIRSF016089; SPC22; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Endoplasmic reticulum; Glycoprotein; Membrane;
KW   Proteomics identification; Reference proteome; Signal-anchor;
KW   Transmembrane; Transmembrane helix.
FT   CHAIN           1..180
FT                   /note="Signal peptidase complex subunit 3"
FT                   /id="PRO_0000218938"
FT   TOPO_DOM        1..11
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000250|UniProtKB:P61008"
FT   TRANSMEM        12..32
FT                   /note="Helical; Signal-anchor for type II membrane protein"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        33..180
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000250|UniProtKB:P61008"
FT   CARBOHYD        141
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000269|PubMed:19159218,
FT                   ECO:0000269|PubMed:34388369"
FT   CONFLICT        68
FT                   /note="F -> S (in Ref. 1; CAB66595)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   180 AA;  20313 MW;  342AB8E0F3F6D71A CRC64;
     MNTVLSRANS LFAFSLSVMA ALTFGCFITT AFKDRSVPVR LHVSRIMLKN VEDFTGPRER
     SDLGFITFDI TADLENIFDW NVKQLFLYLS AEYSTKNNAL NQVVLWDKIV LRGDNPKLLL
     KDMKTKYFFF DDGNGLKGNR NVTLTLSWNV VPNAGILPLV TGSGHVSVPF PDTYEITKSY
//