ID   SPP2A_HUMAN             Reviewed;         520 AA.
AC   Q8TCT8; B2RDS0; Q8TAW1; Q96SZ8;
DT   08-NOV-2002, integrated into UniProtKB/Swiss-Prot.
DT   08-NOV-2002, sequence version 2.
DT   24-JAN-2024, entry version 167.
DE   RecName: Full=Signal peptide peptidase-like 2A {ECO:0000303|PubMed:15385547, ECO:0000312|HGNC:HGNC:30227};
DE            Short=SPP-like 2A {ECO:0000303|PubMed:15385547};
DE            Short=SPPL2a {ECO:0000303|PubMed:15385547};
DE            EC=3.4.23.-;
DE   AltName: Full=Intramembrane protease 3 {ECO:0000303|PubMed:12139484};
DE            Short=IMP-3 {ECO:0000303|PubMed:12139484};
DE   AltName: Full=Presenilin-like protein 2;
DE   Flags: Precursor;
GN   Name=SPPL2A {ECO:0000303|PubMed:15385547,
GN   ECO:0000312|HGNC:HGNC:30227};
GN   Synonyms=IMP3 {ECO:0000303|PubMed:12139484}, PSL2; ORFNames=PSEC0147;
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].
RA   Irmler M., Tomiuk S., Korner M.R., Hofmann K., Conradt M.;
RT   "Characterization of a new protein family with homology to presenilins.";
RL   Submitted (SEP-2001) to the EMBL/GenBank/DDBJ databases.
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Blood;
RX   PubMed=12139484; DOI=10.1023/a:1016365227942;
RA   Grigorenko A.P., Moliaka Y.K., Korovaitseva G.I., Rogaev E.I.;
RT   "Novel class of polytopic proteins with domains associated with putative
RT   protease activity.";
RL   Biochemistry (Mosc.) 67:826-834(2002).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Synovium, and Teratocarcinoma;
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   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Placenta;
RX   PubMed=16303743; DOI=10.1093/dnares/12.2.117;
RA   Otsuki T., Ota T., Nishikawa T., Hayashi K., Suzuki Y., Yamamoto J.,
RA   Wakamatsu A., Kimura K., Sakamoto K., Hatano N., Kawai Y., Ishii S.,
RA   Saito K., Kojima S., Sugiyama T., Ono T., Okano K., Yoshikawa Y.,
RA   Aotsuka S., Sasaki N., Hattori A., Okumura K., Nagai K., Sugano S.,
RA   Isogai T.;
RT   "Signal sequence and keyword trap in silico for selection of full-length
RT   human cDNAs encoding secretion or membrane proteins from oligo-capped cDNA
RT   libraries.";
RL   DNA Res. 12:117-126(2005).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN   [6]
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   [7]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 91-520.
RC   TISSUE=Cervix carcinoma;
RX   PubMed=12077416; DOI=10.1126/science.1070925;
RA   Weihofen A., Binns K., Lemberg M.K., Ashman K., Martoglio B.;
RT   "Identification of signal peptide peptidase, a presenilin-type aspartic
RT   protease.";
RL   Science 296:2215-2218(2002).
RN   [8]
RP   GLYCOSYLATION, TOPOLOGY, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX   PubMed=15385547; DOI=10.1074/jbc.m407898200;
RA   Friedmann E., Lemberg M.K., Weihofen A., Dev K.K., Dengler U., Rovelli G.,
RA   Martoglio B.;
RT   "Consensus analysis of signal peptide peptidase and homologous human
RT   aspartic proteases reveals opposite topology of catalytic domains compared
RT   with presenilins.";
RL   J. Biol. Chem. 279:50790-50798(2004).
RN   [9]
RP   FUNCTION IN CLEAVAGE OF TNF, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP   ASP-412.
RX   PubMed=16829952; DOI=10.1038/ncb1440;
RA   Friedmann E., Hauben E., Maylandt K., Schleeger S., Vreugde S.,
RA   Lichtenthaler S.F., Kuhn P.H., Stauffer D., Rovelli G., Martoglio B.;
RT   "SPPL2a and SPPL2b promote intramembrane proteolysis of TNFalpha in
RT   activated dendritic cells to trigger IL-12 production.";
RL   Nat. Cell Biol. 8:843-848(2006).
RN   [10]
RP   FUNCTION IN CLEAVAGE OF TNF.
RX   PubMed=16829951; DOI=10.1038/ncb1450;
RA   Fluhrer R., Grammer G., Israel L., Condron M.M., Haffner C., Friedmann E.,
RA   Bohland C., Imhof A., Martoglio B., Teplow D.B., Haass C.;
RT   "A gamma-secretase-like intramembrane cleavage of TNFalpha by the GxGD
RT   aspartyl protease SPPL2b.";
RL   Nat. Cell Biol. 8:894-896(2006).
RN   [11]
RP   FUNCTION IN CLEAVAGE OF FASLG, AND MUTAGENESIS OF ASP-412.
RX   PubMed=17557115; DOI=10.1038/sj.cdd.4402175;
RA   Kirkin V., Cahuzac N., Guardiola-Serrano F., Huault S., Luckerath K.,
RA   Friedmann E., Novac N., Wels W.S., Martoglio B., Hueber A.O., Zornig M.;
RT   "The Fas ligand intracellular domain is released by ADAM10 and SPPL2a
RT   cleavage in T-cells.";
RL   Cell Death Differ. 14:1678-1687(2007).
RN   [12]
RP   FUNCTION IN CLEAVAGE OF ITM2B, INTERACTION WITH ITM2B, AND MUTAGENESIS OF
RP   ASP-412.
RX   PubMed=17965014; DOI=10.1074/jbc.m706661200;
RA   Martin L., Fluhrer R., Reiss K., Kremmer E., Saftig P., Haass C.;
RT   "Regulated intramembrane proteolysis of Bri2 (Itm2b) by ADAM10 and
RT   SPPL2a/SPPL2b.";
RL   J. Biol. Chem. 283:1644-1652(2008).
RN   [13]
RP   GLYCOSYLATION AT ASN-155.
RX   PubMed=19139490; DOI=10.1074/mcp.m800504-mcp200;
RA   Jia W., Lu Z., Fu Y., Wang H.P., Wang L.H., Chi H., Yuan Z.F., Zheng Z.B.,
RA   Song L.N., Han H.H., Liang Y.M., Wang J.L., Cai Y., Zhang Y.K., Deng Y.L.,
RA   Ying W.T., He S.M., Qian X.H.;
RT   "A strategy for precise and large scale identification of core fucosylated
RT   glycoproteins.";
RL   Mol. Cell. Proteomics 8:913-923(2009).
RN   [14]
RP   FUNCTION, AND MUTAGENESIS OF ASP-412.
RX   PubMed=23132852; DOI=10.1074/jbc.m112.371369;
RA   Voss M., Fukumori A., Kuhn P.H., Kunzel U., Klier B., Grammer G.,
RA   Haug-Kroper M., Kremmer E., Lichtenthaler S.F., Steiner H., Schroder B.,
RA   Haass C., Fluhrer R.;
RT   "Foamy virus envelope protein is a substrate for signal peptide peptidase-
RT   like 3 (SPPL3).";
RL   J. Biol. Chem. 287:43401-43409(2012).
RN   [15]
RP   INVOLVEMENT IN IMD86.
RX   PubMed=30127434; DOI=10.1038/s41590-018-0178-z;
RA   Kong X.F., Martinez-Barricarte R., Kennedy J., Mele F., Lazarov T.,
RA   Deenick E.K., Ma C.S., Breton G., Lucero K.B., Langlais D., Bousfiha A.,
RA   Aytekin C., Markle J., Trouillet C., Jabot-Hanin F., Arlehamn C.S.L.,
RA   Rao G., Picard C., Lasseau T., Latorre D., Hambleton S., Deswarte C.,
RA   Itan Y., Abarca K., Moraes-Vasconcelos D., Ailal F., Ikinciogullari A.,
RA   Dogu F., Benhsaien I., Sette A., Abel L., Boisson-Dupuis S., Schroeder B.,
RA   Nussenzweig M.C., Liu K., Geissmann F., Tangye S.G., Gros P., Sallusto F.,
RA   Bustamante J., Casanova J.L.;
RT   "Disruption of an antimycobacterial circuit between dendritic and helper T
RT   cells in human SPPL2a deficiency.";
RL   Nat. Immunol. 19:973-985(2018).
CC   -!- FUNCTION: Intramembrane-cleaving aspartic protease (I-CLiP) that
CC       cleaves type II membrane signal peptides in the hydrophobic plane of
CC       the membrane. Functions in FASLG, ITM2B and TNF processing
CC       (PubMed:16829952, PubMed:16829951, PubMed:17557115, PubMed:17965014).
CC       Catalyzes the intramembrane cleavage of the anchored fragment of shed
CC       TNF-alpha (TNF), which promotes the release of the intracellular domain
CC       (ICD) for signaling to the nucleus (PubMed:16829952). Also responsible
CC       for the intramembrane cleavage of Fas antigen ligand FASLG, which
CC       promotes the release of the intracellular FasL domain (FasL ICD)
CC       (PubMed:17557115). Essential for degradation of the invariant chain
CC       CD74 that plays a central role in the function of antigen-presenting
CC       cells in the immune system (By similarity). Plays a role in the
CC       regulation of innate and adaptive immunity (PubMed:16829952). Catalyzes
CC       the intramembrane cleavage of the simian foamy virus envelope
CC       glycoprotein gp130 independently of prior ectodomain shedding by furin
CC       or furin-like proprotein convertase (PC)-mediated cleavage proteolysis
CC       (PubMed:23132852). {ECO:0000250|UniProtKB:Q9JJF9,
CC       ECO:0000269|PubMed:16829951, ECO:0000269|PubMed:16829952,
CC       ECO:0000269|PubMed:17557115, ECO:0000269|PubMed:17965014,
CC       ECO:0000269|PubMed:23132852}.
CC   -!- SUBUNIT: Interacts with ITM2B (PubMed:17965014).
CC       {ECO:0000269|PubMed:17965014}.
CC   -!- INTERACTION:
CC       Q8TCT8; O43765: SGTA; NbExp=7; IntAct=EBI-750784, EBI-347996;
CC       Q8TCT8; O76024: WFS1; NbExp=3; IntAct=EBI-750784, EBI-720609;
CC   -!- SUBCELLULAR LOCATION: Late endosome membrane
CC       {ECO:0000269|PubMed:16829952}; Multi-pass membrane protein
CC       {ECO:0000305}. Lysosome membrane {ECO:0000250|UniProtKB:Q9JJF9}; Multi-
CC       pass membrane protein {ECO:0000250|UniProtKB:Q9JJF9}. Membrane
CC       {ECO:0000269|PubMed:15385547}; Multi-pass membrane protein
CC       {ECO:0000305}; Lumenal side {ECO:0000269|PubMed:15385547}.
CC       Note=Colocalizes with palmitoylated and myristoylated proteins at the
CC       plasma membrane.
CC   -!- TISSUE SPECIFICITY: Ubiquitous. {ECO:0000269|PubMed:15385547}.
CC   -!- DOMAIN: The PAL motif is required for normal active site conformation.
CC       The catalytic domains embedded in the membrane are in the opposite
CC       orientation to that of the presenilin protein family; therefore, it is
CC       predicted to cleave type II-oriented substrate peptides like the
CC       prototypic protease SPP. The C-terminal tail is necessary for lysosomal
CC       transport. {ECO:0000250|UniProtKB:P49768,
CC       ECO:0000250|UniProtKB:Q9JJF9}.
CC   -!- PTM: Glycosylated. {ECO:0000269|PubMed:15385547,
CC       ECO:0000269|PubMed:19139490}.
CC   -!- DISEASE: Immunodeficiency 86 (IMD86) [MIM:619549]: An autosomal
CC       recessive disorder characterized by susceptibility to mycobacterial
CC       disease after exposure to BCG vaccine. Affected individuals usually
CC       develop localized mycobacterial lymphadenopathy.
CC       {ECO:0000269|PubMed:30127434}. Note=The disease is caused by variants
CC       affecting the gene represented in this entry.
CC   -!- SIMILARITY: Belongs to the peptidase A22B family. {ECO:0000305}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=BAB55117.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC       Sequence=CAD13133.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR   EMBL; AJ345028; CAC87789.1; -; mRNA.
DR   EMBL; AY169314; AAO12539.1; -; mRNA.
DR   EMBL; AK027446; BAB55117.1; ALT_INIT; mRNA.
DR   EMBL; AK315651; BAG38017.1; -; mRNA.
DR   EMBL; AK075454; BAC11630.1; -; mRNA.
DR   EMBL; CH471082; EAW77410.1; -; Genomic_DNA.
DR   EMBL; BC025740; AAH25740.1; -; mRNA.
DR   EMBL; AJ420896; CAD13133.1; ALT_INIT; mRNA.
DR   CCDS; CCDS10138.1; -.
DR   RefSeq; NP_116191.2; NM_032802.3.
DR   AlphaFoldDB; Q8TCT8; -.
DR   BioGRID; 124328; 11.
DR   IntAct; Q8TCT8; 6.
DR   MINT; Q8TCT8; -.
DR   STRING; 9606.ENSP00000261854; -.
DR   BindingDB; Q8TCT8; -.
DR   ChEMBL; CHEMBL4105833; -.
DR   MEROPS; A22.007; -.
DR   TCDB; 1.A.54.3.2; the presenilin er ca(2+) leak channel (presenilin) family.
DR   GlyConnect; 1746; 4 N-Linked glycans (1 site).
DR   GlyCosmos; Q8TCT8; 7 sites, 4 glycans.
DR   GlyGen; Q8TCT8; 8 sites, 4 N-linked glycans (1 site), 1 O-linked glycan (1 site).
DR   iPTMnet; Q8TCT8; -.
DR   PhosphoSitePlus; Q8TCT8; -.
DR   SwissPalm; Q8TCT8; -.
DR   BioMuta; SPPL2A; -.
DR   DMDM; 25008981; -.
DR   EPD; Q8TCT8; -.
DR   jPOST; Q8TCT8; -.
DR   MassIVE; Q8TCT8; -.
DR   MaxQB; Q8TCT8; -.
DR   PaxDb; 9606-ENSP00000261854; -.
DR   PeptideAtlas; Q8TCT8; -.
DR   ProteomicsDB; 74164; -.
DR   Pumba; Q8TCT8; -.
DR   Antibodypedia; 24774; 129 antibodies from 24 providers.
DR   DNASU; 84888; -.
DR   Ensembl; ENST00000261854.10; ENSP00000261854.5; ENSG00000138600.11.
DR   GeneID; 84888; -.
DR   KEGG; hsa:84888; -.
DR   MANE-Select; ENST00000261854.10; ENSP00000261854.5; NM_032802.4; NP_116191.2.
DR   UCSC; uc001zyv.4; human.
DR   AGR; HGNC:30227; -.
DR   CTD; 84888; -.
DR   DisGeNET; 84888; -.
DR   GeneCards; SPPL2A; -.
DR   HGNC; HGNC:30227; SPPL2A.
DR   HPA; ENSG00000138600; Low tissue specificity.
DR   MalaCards; SPPL2A; -.
DR   MIM; 608238; gene.
DR   MIM; 619549; phenotype.
DR   neXtProt; NX_Q8TCT8; -.
DR   OpenTargets; ENSG00000138600; -.
DR   VEuPathDB; HostDB:ENSG00000138600; -.
DR   eggNOG; KOG2442; Eukaryota.
DR   GeneTree; ENSGT00940000157722; -.
DR   HOGENOM; CLU_023799_2_1_1; -.
DR   InParanoid; Q8TCT8; -.
DR   OMA; QWGPCHF; -.
DR   OrthoDB; 907832at2759; -.
DR   PhylomeDB; Q8TCT8; -.
DR   TreeFam; TF319186; -.
DR   BRENDA; 3.4.23.B24; 2681.
DR   PathwayCommons; Q8TCT8; -.
DR   Reactome; R-HSA-5357905; Regulation of TNFR1 signaling.
DR   SignaLink; Q8TCT8; -.
DR   BioGRID-ORCS; 84888; 11 hits in 1121 CRISPR screens.
DR   ChiTaRS; SPPL2A; human.
DR   GeneWiki; SPPL2A; -.
DR   GenomeRNAi; 84888; -.
DR   Pharos; Q8TCT8; Tchem.
DR   PRO; PR:Q8TCT8; -.
DR   Proteomes; UP000005640; Chromosome 15.
DR   RNAct; Q8TCT8; Protein.
DR   Bgee; ENSG00000138600; Expressed in ileal mucosa and 190 other cell types or tissues.
DR   ExpressionAtlas; Q8TCT8; baseline and differential.
DR   GO; GO:0098554; C:cytoplasmic side of endoplasmic reticulum membrane; IDA:UniProtKB.
DR   GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR   GO; GO:0030660; C:Golgi-associated vesicle membrane; IDA:UniProtKB.
DR   GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA.
DR   GO; GO:0005770; C:late endosome; IDA:UniProtKB.
DR   GO; GO:0031902; C:late endosome membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0098553; C:lumenal side of endoplasmic reticulum membrane; IDA:UniProtKB.
DR   GO; GO:0005765; C:lysosomal membrane; HDA:UniProtKB.
DR   GO; GO:0016020; C:membrane; IDA:UniProtKB.
DR   GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR   GO; GO:0042500; F:aspartic endopeptidase activity, intramembrane cleaving; IDA:UniProtKB.
DR   GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR   GO; GO:0006509; P:membrane protein ectodomain proteolysis; IDA:UniProtKB.
DR   GO; GO:0031293; P:membrane protein intracellular domain proteolysis; IDA:UniProtKB.
DR   GO; GO:0033619; P:membrane protein proteolysis; IDA:UniProtKB.
DR   GO; GO:0050776; P:regulation of immune response; IMP:UniProtKB.
DR   GO; GO:0010803; P:regulation of tumor necrosis factor-mediated signaling pathway; TAS:Reactome.
DR   CDD; cd02129; PA_hSPPL_like; 1.
DR   Gene3D; 3.50.30.30; -; 1.
DR   InterPro; IPR046450; PA_dom_sf.
DR   InterPro; IPR003137; PA_domain.
DR   InterPro; IPR007369; Peptidase_A22B_SPP.
DR   InterPro; IPR006639; Preselin/SPP.
DR   PANTHER; PTHR12174; SIGNAL PEPTIDE PEPTIDASE; 1.
DR   PANTHER; PTHR12174:SF34; SIGNAL PEPTIDE PEPTIDASE-LIKE 2A; 1.
DR   Pfam; PF02225; PA; 1.
DR   Pfam; PF04258; Peptidase_A22B; 1.
DR   SMART; SM00730; PSN; 1.
DR   SUPFAM; SSF52025; PA domain; 1.
DR   Genevisible; Q8TCT8; HS.
PE   1: Evidence at protein level;
KW   Endosome; Glycoprotein; Hydrolase; Lysosome; Membrane; Protease;
KW   Reference proteome; Signal; Transmembrane; Transmembrane helix.
FT   SIGNAL          1..25
FT                   /evidence="ECO:0000269|PubMed:15385547"
FT   CHAIN           26..520
FT                   /note="Signal peptide peptidase-like 2A"
FT                   /id="PRO_0000073910"
FT   TOPO_DOM        26..172
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000269|PubMed:15385547"
FT   TRANSMEM        173..193
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        194..220
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        221..241
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        242..247
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        248..268
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        269..285
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        286..306
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        307..311
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        312..332
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        333..340
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        341..361
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        362..399
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000269|PubMed:15385547"
FT   TRANSMEM        400..420
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        421..437
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        438..458
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        459..460
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        461..481
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        482..520
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000269|PubMed:15385547"
FT   DOMAIN          63..151
FT                   /note="PA"
FT   MOTIF           463..465
FT                   /note="PAL"
FT   MOTIF           495..498
FT                   /note="YXXo lysosomal targeting motif"
FT   ACT_SITE        351
FT                   /evidence="ECO:0000250|UniProtKB:P49810"
FT   ACT_SITE        412
FT                   /evidence="ECO:0000250|UniProtKB:P49810"
FT   CARBOHYD        58
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        66
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        74
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        116
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        126
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        149
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        155
FT                   /note="N-linked (GlcNAc...) (complex) asparagine"
FT                   /evidence="ECO:0000269|PubMed:19139490"
FT   VARIANT         90
FT                   /note="V -> I (in dbSNP:rs8034443)"
FT                   /id="VAR_051790"
FT   MUTAGEN         412
FT                   /note="D->A: Loss of intramembrane-cleaving activity toward
FT                   FASLG, ITM2B, TNF and the simian foamy virus envelope
FT                   glycoprotein gp130."
FT                   /evidence="ECO:0000269|PubMed:16829952,
FT                   ECO:0000269|PubMed:17557115, ECO:0000269|PubMed:17965014,
FT                   ECO:0000269|PubMed:23132852"
FT   CONFLICT        126
FT                   /note="N -> D (in Ref. 3; BAB55117)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        271
FT                   /note="I -> T (in Ref. 4; BAC11630)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        406
FT                   /note="S -> L (in Ref. 4; BAC11630)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        446
FT                   /note="I -> F (in Ref. 4; BAC11630)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        511
FT                   /note="V -> E (in Ref. 3; BAB55117)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   520 AA;  58143 MW;  A7A933A6504507DC CRC64;
     MGPQRRLSPA GAALLWGFLL QLTAAQEAIL HASGNGTTKD YCMLYNPYWT ALPSTLENAT
     SISLMNLTST PLCNLSDIPP VGIKSKAVVV PWGSCHFLEK ARIAQKGGAE AMLVVNNSVL
     FPPSGNRSEF PDVKILIAFI SYKDFRDMNQ TLGDNITVKM YSPSWPNFDY TMVVIFVIAV
     FTVALGGYWS GLVELENLKA VTTEDREMRK KKEEYLTFSP LTVVIFVVIC CVMMVLLYFF
     YKWLVYVMIA IFCIASAMSL YNCLAALIHK IPYGQCTIAC RGKNMEVRLI FLSGLCIAVA
     VVWAVFRNED RWAWILQDIL GIAFCLNLIK TLKLPNFKSC VILLGLLLLY DVFFVFITPF
     ITKNGESIMV ELAAGPFGNN EKLPVVIRVP KLIYFSVMSV CLMPVSILGF GDIIVPGLLI
     AYCRRFDVQT GSSYIYYVSS TVAYAIGMIL TFVVLVLMKK GQPALLYLVP CTLITASVVA
     WRRKEMKKFW KGNSYQMMDH LDCATNEENP VISGEQIVQQ
//