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Protein

Signal peptide peptidase-like 3

Gene

SPPL3

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-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 sitei201By similarity1
Active sitei272By 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 NFAT protein import into nucleus Source: UniProtKB
  • positive regulation of protein binding Source: UniProtKB
  • positive regulation of protein dephosphorylation Source: UniProtKB
  • signal peptide processing Source: GO_Central
  • T cell receptor signaling pathway Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Hydrolase, Protease

Enzyme and pathway databases

BioCyciZFISH:ENSG00000157837-MONOMER.

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

HGNCiHGNC:30424. SPPL3.

Subcellular locationi

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 8Lumenal1 Publication8
Transmembranei9 – 29HelicalSequence analysisAdd BLAST21
Topological domaini30 – 75Cytoplasmic1 PublicationAdd BLAST46
Transmembranei76 – 96HelicalSequence analysisAdd BLAST21
Topological domaini97 – 98LumenalSequence analysis2
Transmembranei99 – 119HelicalSequence analysisAdd BLAST21
Topological domaini120 – 137CytoplasmicSequence analysisAdd BLAST18
Transmembranei138 – 160HelicalSequence analysisAdd BLAST23
Topological domaini161 – 165LumenalSequence analysis5
Transmembranei166 – 186HelicalSequence analysisAdd BLAST21
Topological domaini187 – 191CytoplasmicSequence analysis5
Transmembranei192 – 212HelicalSequence analysisAdd BLAST21
Topological domaini213 – 263Lumenal1 PublicationAdd BLAST51
Transmembranei264 – 284HelicalSequence analysisAdd BLAST21
Topological domaini285 – 312CytoplasmicSequence analysisAdd BLAST28
Transmembranei313 – 333HelicalSequence analysisAdd BLAST21
Topological domaini334 – 340LumenalSequence analysis7
Transmembranei341 – 361HelicalSequence analysisAdd BLAST21
Topological domaini362 – 385Cytoplasmic1 PublicationAdd BLAST24

GO - Cellular componenti

  • endoplasmic reticulum-Golgi intermediate compartment membrane Source: UniProtKB
  • Golgi-associated vesicle membrane Source: UniProtKB
  • integral component of cytoplasmic side of endoplasmic reticulum membrane Source: UniProtKB
  • integral component of lumenal side of endoplasmic reticulum membrane Source: UniProtKB
  • intracellular membrane-bounded organelle Source: HPA
  • lysosomal membrane Source: GO_Central
  • membrane Source: UniProtKB
  • plasma membrane Source: HPA
  • rough endoplasmic reticulum Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Endoplasmic reticulum, Golgi apparatus, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi201D → A: Does not affect complex glycosylation pattern of cellular glycoproteins; when associated with A-272. 1 Publication1
Mutagenesisi272D → 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-201. 2 Publications1

Organism-specific databases

DisGeNETi121665.
OpenTargetsiENSG00000157837.

Polymorphism and mutation databases

BioMutaiSPPL3.
DMDMi25008979.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000739121 – 385Signal peptide peptidase-like 3Add BLAST385

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. 17 interactors.
STRINGi9606.ENSP00000288680.

Structurei

3D structure databases

ProteinModelPortaliQ8TCT6.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi342 – 344PAL3

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi375 – 380Poly-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.
OMAiELWEGPA.
OrthoDBiEOG091G0EHF.
PhylomeDBiQ8TCT6.
TreeFamiTF323842.

Family and domain databases

InterProiIPR007369. Peptidase_A22B_SPP.
IPR006639. Preselin/SPP.
[Graphical view]
PANTHERiPTHR12174. PTHR12174. 1 hit.
PfamiPF04258. Peptidase_A22B. 1 hit.
[Graphical view]
SMARTiSM00730. PSN. 1 hit.
[Graphical view]

Sequences (3)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Note: Experimental confirmation may be lacking for some isoforms.
Isoform 1 (identifier: Q8TCT6-1) [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
SSSGSFNGEQ EPIIGFQPMD STRARFLPMG ACVSLLVMFF FFDSVQVVFT
110 120 130 140 150
ICTAVLATIA FAFLLLPMCQ YLTRPCSPQN KISFGCCGRF TAAELLSFSL
160 170 180 190 200
SVMLVLIWVL TGHWLLMDAL AMGLCVAMIA FVRLPSLKVS CLLLSGLLIY
210 220 230 240 250
DVFWVFFSAY IFNSNVMVKV ATQPADNPLD VLSRKLHLGP NVGRDVPRLS
260 270 280 290 300
LPGKLVFPSS TGSHFSMLGI GDIVMPGLLL CFVLRYDNYK KQASGDSCGA
310 320 330 340 350
PGPANISGRM QKVSYFHCTL IGYFVGLLTA TVASRIHRAA QPALLYLVPF
360 370 380
TLLPLLTMAY LKGDLRRMWS EPFHSKSSSS RFLEV
Length:385
Mass (Da):42,563
Last modified:June 1, 2002 - v1
Checksum:iBF829565E14A2996
GO
Isoform 2 (identifier: Q8TCT6-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     59-82: EQEPIIGFQPMDSTRARFLPMGAC → NSTNNSIQTIDSTQALFLPIGAS

Show »
Length:384
Mass (Da):42,261
Checksum:i04D8C036355B32A1
GO
Isoform 3 (identifier: Q8TCT6-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-216: 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 conflicti140F → Y in BAC11290 (PubMed:14702039).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0052051 – 216Missing in isoform 3. 1 PublicationAdd BLAST216
Alternative sequenceiVSP_00520659 – 82EQEPI…PMGAC → NSTNNSIQTIDSTQALFLPI GAS in isoform 2. 4 PublicationsAdd BLAST24

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. [Q8TCT6-1]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

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.

3D structure databases

ProteinModelPortaliQ8TCT6.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi125743. 17 interactors.
STRINGi9606.ENSP00000288680.

Protein family/group databases

MEROPSiA22.005.

PTM databases

SwissPalmiQ8TCT6.

Polymorphism and mutation databases

BioMutaiSPPL3.
DMDMi25008979.

Proteomic databases

MaxQBiQ8TCT6.
PaxDbiQ8TCT6.
PeptideAtlasiQ8TCT6.
PRIDEiQ8TCT6.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000353487; ENSP00000288680; ENSG00000157837. [Q8TCT6-2]
GeneIDi121665.
KEGGihsa:121665.
UCSCiuc001tzd.4. human. [Q8TCT6-1]

Organism-specific databases

CTDi121665.
DisGeNETi121665.
GeneCardsiSPPL3.
HGNCiHGNC:30424. SPPL3.
HPAiHPA004194.
HPA059958.
MIMi608240. gene.
neXtProtiNX_Q8TCT6.
OpenTargetsiENSG00000157837.
GenAtlasiSearch...

Phylogenomic databases

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

Enzyme and pathway databases

BioCyciZFISH:ENSG00000157837-MONOMER.

Miscellaneous databases

ChiTaRSiSPPL3. human.
GeneWikiiUNQ1887.
GenomeRNAii121665.
PROiQ8TCT6.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000157837.
ExpressionAtlasiQ8TCT6. baseline and differential.
GenevisibleiQ8TCT6. HS.

Family and domain databases

InterProiIPR007369. Peptidase_A22B_SPP.
IPR006639. Preselin/SPP.
[Graphical view]
PANTHERiPTHR12174. PTHR12174. 1 hit.
PfamiPF04258. Peptidase_A22B. 1 hit.
[Graphical view]
SMARTiSM00730. PSN. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiSPPL3_HUMAN
AccessioniPrimary (citable) accession number: Q8TCT6
Secondary accession number(s): Q3MJ04, Q8TAU4, Q96DD9
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 8, 2002
Last sequence update: June 1, 2002
Last modified: November 2, 2016
This is version 129 of the entry and version 1 of the sequence. [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

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.