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Protein

Signal peptide peptidase-like 3

Gene

SPPL3

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Intramembrane-cleaving aspartic protease (I-CLiP) that cleaves type II membrane protein substrates in or close to their luminal transmembrane domain boundaries (PubMed:16873890, PubMed:25354954, PubMed:25827571). Acts like a sheddase by mediating the proteolytic release and secretion of active site-containing ectodomains of glycan-modifiying glycosidase and glycosyltransferase enzymes such as MGAT5, B4GAT1 and B4GALT1 (PubMed:25354954, PubMed:25827571). Catalyzes the intramembrane cleavage of the envelope glycoprotein gp130 and/or the leader peptide gp18LP of the simian foamy virus independent of prior ectodomain shedding by furin or furin-like proprotein convertase (PC)-mediated cleavage proteolysis (PubMed:23132852). May also have the ability to serve as a shedding protease for subsequent intramembrane proteolysis by SPPL2A and SPPL2B of the envelope glycoprotein gp130 (PubMed:23132852). Plays a role in the regulation of cellular glycosylation processes (PubMed:25354954). Required to link T-cell antigen receptor (TCR) and calcineurin-NFAT signaling cascades in lymphocytes by promoting the association of STIM1 and ORAI1 during store-operated calcium entry (SOCE) in a protease-independent manner (PubMed:25384971).5 Publications

Enzyme regulationi

Its proteolytic activity is blocked by a signal peptide peptidase (SPP) inhibitor, (ZLL)2-ketone (ZLL) or a gamma-secretase inhibitor, LY411,575 (PubMed:16873890). However, is not inhibited by ZLL and LY411,575 for activity on simian foamy virus envelope glycoprotein gp130 (PubMed:23132852).2 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Active sitei200By similarity1
Active sitei271By similarity1

GO - Molecular functioni

  • aspartic endopeptidase activity, intramembrane cleaving Source: UniProtKB
  • protein homodimerization activity Source: UniProtKB

GO - Biological processi

  • membrane protein proteolysis Source: UniProtKB
  • positive regulation of calcineurin-NFAT signaling cascade Source: UniProtKB
  • positive regulation of cytosolic calcium ion concentration Source: UniProtKB
  • positive regulation of protein binding Source: UniProtKB
  • positive regulation of protein dephosphorylation Source: UniProtKB
  • T cell receptor signaling pathway Source: UniProtKB

Keywordsi

Molecular functionHydrolase, Protease

Protein family/group databases

MEROPSiA22.005

Names & Taxonomyi

Protein namesi
Recommended name:
Signal peptide peptidase-like 31 PublicationImported (EC:3.4.23.-)
Short name:
SPP-like 31 Publication
Alternative name(s):
Intramembrane protease 21 Publication
Short name:
IMP-21 Publication
Presenilin homologous protein 11 Publication
Short name:
PSH11 Publication
Presenilin-like protein 41 Publication
Gene namesi
Name:SPPL31 PublicationImported
Synonyms:IMP21 Publication, PSL41 Publication
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 12

Organism-specific databases

EuPathDBiHostDB:ENSG00000157837.15
HGNCiHGNC:30424 SPPL3
MIMi608240 gene
neXtProtiNX_Q8TCT6

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 8Lumenal1 Publication8
Transmembranei9 – 29HelicalSequence analysisAdd BLAST21
Topological domaini30 – 74Cytoplasmic1 PublicationAdd BLAST45
Transmembranei75 – 95HelicalSequence analysisAdd BLAST21
Topological domaini96 – 97LumenalSequence analysis2
Transmembranei98 – 118HelicalSequence analysisAdd BLAST21
Topological domaini119 – 136CytoplasmicSequence analysisAdd BLAST18
Transmembranei137 – 159HelicalSequence analysisAdd BLAST23
Topological domaini160 – 164LumenalSequence analysis5
Transmembranei165 – 185HelicalSequence analysisAdd BLAST21
Topological domaini186 – 190CytoplasmicSequence analysis5
Transmembranei191 – 211HelicalSequence analysisAdd BLAST21
Topological domaini212 – 262Lumenal1 PublicationAdd BLAST51
Transmembranei263 – 283HelicalSequence analysisAdd BLAST21
Topological domaini284 – 311CytoplasmicSequence analysisAdd BLAST28
Transmembranei312 – 332HelicalSequence analysisAdd BLAST21
Topological domaini333 – 339LumenalSequence analysis7
Transmembranei340 – 360HelicalSequence analysisAdd BLAST21
Topological domaini361 – 384Cytoplasmic1 PublicationAdd BLAST24

Keywords - Cellular componenti

Endoplasmic reticulum, Golgi apparatus, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi200D → A: Does not affect complex glycosylation pattern of cellular glycoproteins; when associated with A-271. 1 Publication1
Mutagenesisi271D → A: Loss of intramembrane-cleaving activity toward the simian foamy virus envelope glycoprotein gp130. Does not affect complex glycosylation pattern of cellular glycoproteins; when associated with A-200. 2 Publications1

Organism-specific databases

DisGeNETi121665
OpenTargetsiENSG00000157837

Polymorphism and mutation databases

BioMutaiSPPL3
DMDMi25008979

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000739121 – 384Signal peptide peptidase-like 3Add BLAST384

Post-translational modificationi

Not glycosylated (PubMed:15385547, PubMed:15998642).2 Publications

Proteomic databases

MaxQBiQ8TCT6
PaxDbiQ8TCT6
PeptideAtlasiQ8TCT6
PRIDEiQ8TCT6

PTM databases

SwissPalmiQ8TCT6

Expressioni

Tissue specificityi

Widely expressed (PubMed:15385547). Expressed in the brain (PubMed:11978763).2 Publications

Gene expression databases

BgeeiENSG00000157837
ExpressionAtlasiQ8TCT6 baseline and differential
GenevisibleiQ8TCT6 HS

Organism-specific databases

HPAiHPA004194
HPA059958

Interactioni

Subunit structurei

Monomer (PubMed:15385547, PubMed:15998642, PubMed:16873890). Homodimer (PubMed:15385547, PubMed:15998642, PubMed:16873890). Interacts with STIM1 (via the transmembrane region and the SOAR/CAD domain); the interaction promotes the binding of STIM1 to ORAI1 (PubMed:25384971). Interacts with the simian foamy virus envelope glycoprotein gp130 and its processed leader peptide gp18LP; preferentially interacts with the envelope glycoprotein gp130 (PubMed:23132852).By similarity5 Publications

GO - Molecular functioni

  • protein homodimerization activity Source: UniProtKB

Protein-protein interaction databases

BioGridi125743, 20 interactors
STRINGi9606.ENSP00000288680

Structurei

3D structure databases

ProteinModelPortaliQ8TCT6
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi341 – 343PAL3

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi374 – 379Poly-Ser6

Domaini

The first transmembrane domain may act as a type I signal anchor (PubMed:15385547). The catalytic loops is exposed toward the lumen (PubMed:15385547). The PAL motif is required for normal active site conformation. The catalytic domains embedded in the membrane are in the opposite orientation to that of the presenilin protein family (By similarity).By similarity1 Publication

Sequence similaritiesi

Belongs to the peptidase A22B family.Curated

Keywords - Domaini

Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG2443 Eukaryota
ENOG410XTES LUCA
GeneTreeiENSGT00530000062920
HOGENOMiHOG000243413
HOVERGENiHBG023986
InParanoidiQ8TCT6
KOiK09598
OMAiCGRFTGA
OrthoDBiEOG091G0EHF
PhylomeDBiQ8TCT6
TreeFamiTF323842

Family and domain databases

InterProiView protein in InterPro
IPR007369 Peptidase_A22B_SPP
IPR006639 Preselin/SPP
PANTHERiPTHR12174 PTHR12174, 1 hit
PfamiView protein in Pfam
PF04258 Peptidase_A22B, 1 hit
SMARTiView protein in SMART
SM00730 PSN, 1 hit

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 2 (identifier: Q8TCT6-2) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MAEQTYSWAY SLVDSSQVST FLISILLIVY GSFRSLNMDF ENQDKEKDSN
60 70 80 90 100
SSSGSFNGNS TNNSIQTIDS TQALFLPIGA SVSLLVMFFF FDSVQVVFTI
110 120 130 140 150
CTAVLATIAF AFLLLPMCQY LTRPCSPQNK ISFGCCGRFT AAELLSFSLS
160 170 180 190 200
VMLVLIWVLT GHWLLMDALA MGLCVAMIAF VRLPSLKVSC LLLSGLLIYD
210 220 230 240 250
VFWVFFSAYI FNSNVMVKVA TQPADNPLDV LSRKLHLGPN VGRDVPRLSL
260 270 280 290 300
PGKLVFPSST GSHFSMLGIG DIVMPGLLLC FVLRYDNYKK QASGDSCGAP
310 320 330 340 350
GPANISGRMQ KVSYFHCTLI GYFVGLLTAT VASRIHRAAQ PALLYLVPFT
360 370 380
LLPLLTMAYL KGDLRRMWSE PFHSKSSSSR FLEV
Length:384
Mass (Da):42,261
Last modified:March 28, 2018 - v2
Checksum:i04D8C036355B32A1
GO
Isoform 3 (identifier: Q8TCT6-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-215: Missing.

Show »
Length:169
Mass (Da):18,478
Checksum:i7A97E2C1713CB938
GO

Sequence cautioni

The sequence BAC11290 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti59 – 81NSTNN…PIGAS → EQEPIIGFQPMDSTRARFLP MGAC in CAD13135 (PubMed:12077416).CuratedAdd BLAST23
Sequence conflicti139F → Y in BAC11290 (PubMed:14702039).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0052051 – 215Missing in isoform 3. 1 PublicationAdd BLAST215

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AJ345030 mRNA Translation: CAC87791.1
AJ420898 mRNA Translation: CAD13135.1
AY169313 mRNA Translation: AAO12538.1
AB252457 mRNA Translation: BAF30928.1
CH471054 Genomic DNA Translation: EAW98220.1
BC009551 mRNA Translation: AAH09551.1
BC025781 mRNA Translation: AAH25781.1
BC073910 mRNA Translation: AAH73910.1
BC101625 mRNA Translation: AAI01626.1
BC101627 mRNA Translation: AAI01628.1
AK074916 mRNA Translation: BAC11290.1 Different initiation.
CCDSiCCDS9208.1 [Q8TCT6-2]
RefSeqiNP_620584.2, NM_139015.4 [Q8TCT6-2]
UniGeneiHs.507087
Hs.683964

Genome annotation databases

EnsembliENST00000353487; ENSP00000288680; ENSG00000157837 [Q8TCT6-2]
GeneIDi121665
KEGGihsa:121665
UCSCiuc001tzd.4 human [Q8TCT6-2]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiSPPL3_HUMAN
AccessioniPrimary (citable) accession number: Q8TCT6
Secondary accession number(s): Q3MJ04, Q8TAU4, Q96DD9
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 8, 2002
Last sequence update: March 28, 2018
Last modified: May 23, 2018
This is version 139 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 12
    Human chromosome 12: entries, gene names and cross-references to MIM
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. Peptidase families
    Classification of peptidase families and list of entries
  4. SIMILARITY comments
    Index of protein domains and families

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