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Protein

Signal peptide peptidase-like 2A

Gene

SPPL2A

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 signal peptides in the hydrophobic plane of the membrane. Functions in FASLG, ITM2B and TNF processing (PubMed:16829952, PubMed:16829951, PubMed:17557115, PubMed:17965014). Catalyzes the intramembrane cleavage of the anchored fragment of shed TNF-alpha (TNF), which promotes the release of the intracellular domain (ICD) for signaling to the nucleus (PubMed:16829952). Also responsible for the intramembrane cleavage of Fas antigen ligand FASLG, which promotes the release of the intracellular FasL domain (FasL ICD) (PubMed:17557115). May play a role in the regulation of innate and adaptive immunity (PubMed:16829952). Catalyzes the intramembrane cleavage of the simian foamy virus envelope glycoprotein gp130 independently of prior ectodomain shedding by furin or furin-like proprotein convertase (PC)-mediated cleavage proteolysis (PubMed:23132852).5 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Active sitei351By similarity1
Active sitei412By similarity1

GO - Molecular functioni

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

GO - Biological processi

  • membrane protein ectodomain proteolysis Source: UniProtKB
  • membrane protein intracellular domain proteolysis Source: UniProtKB
  • membrane protein proteolysis Source: UniProtKB
  • regulation of immune response Source: UniProtKB
  • signal peptide processing Source: GO_Central
Complete GO annotation...

Keywords - Molecular functioni

Hydrolase, Protease

Enzyme and pathway databases

BioCyciZFISH:ENSG00000138600-MONOMER.
ReactomeiR-HSA-5357905. Regulation of TNFR1 signaling.

Protein family/group databases

MEROPSiA22.007.
TCDBi1.A.54.3.2. the presenilin er ca(2+) leak channel (presenilin) family.

Names & Taxonomyi

Protein namesi
Recommended name:
Signal peptide peptidase-like 2A1 PublicationImported (EC:3.4.23.-)
Short name:
SPP-like 2A1 Publication
Short name:
SPPL2a1 Publication
Alternative name(s):
Intramembrane protease 31 Publication
Short name:
IMP-31 Publication
Presenilin-like protein 2
Gene namesi
Name:SPPL2A1 PublicationImported
Synonyms:IMP31 Publication, PSL2
ORF Names:PSEC0147
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 15

Organism-specific databases

HGNCiHGNC:30227. SPPL2A.

Subcellular locationi

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini26 – 172Lumenal1 PublicationAdd BLAST147
Transmembranei173 – 193HelicalSequence analysisAdd BLAST21
Topological domaini194 – 220CytoplasmicSequence analysisAdd BLAST27
Transmembranei221 – 241HelicalSequence analysisAdd BLAST21
Topological domaini242 – 247LumenalSequence analysis6
Transmembranei248 – 268HelicalSequence analysisAdd BLAST21
Topological domaini269 – 285CytoplasmicSequence analysisAdd BLAST17
Transmembranei286 – 306HelicalSequence analysisAdd BLAST21
Topological domaini307 – 311LumenalSequence analysis5
Transmembranei312 – 332HelicalSequence analysisAdd BLAST21
Topological domaini333 – 340CytoplasmicSequence analysis8
Transmembranei341 – 361HelicalSequence analysisAdd BLAST21
Topological domaini362 – 399Lumenal1 PublicationAdd BLAST38
Transmembranei400 – 420HelicalSequence analysisAdd BLAST21
Topological domaini421 – 437CytoplasmicSequence analysisAdd BLAST17
Transmembranei438 – 458HelicalSequence analysisAdd BLAST21
Topological domaini459 – 460LumenalSequence analysis2
Transmembranei461 – 481HelicalSequence analysisAdd BLAST21
Topological domaini482 – 520Cytoplasmic1 PublicationAdd BLAST39

GO - Cellular componenti

  • extracellular exosome 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
  • late endosome Source: UniProtKB
  • late endosome membrane Source: UniProtKB-SubCell
  • lysosomal membrane Source: UniProtKB
  • membrane Source: UniProtKB
  • plasma membrane Source: HPA
Complete GO annotation...

Keywords - Cellular componenti

Endosome, Lysosome, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi412D → A: Loss of intramembrane-cleaving activity toward FASLG, ITM2B, TNF and the simian foamy virus envelope glycoprotein gp130. 4 Publications1

Organism-specific databases

DisGeNETi84888.
OpenTargetsiENSG00000138600.

Polymorphism and mutation databases

BioMutaiSPPL2A.
DMDMi25008981.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 251 PublicationAdd BLAST25
ChainiPRO_000007391026 – 520Signal peptide peptidase-like 2AAdd BLAST495

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Glycosylationi58N-linked (GlcNAc...)Sequence analysis1
Glycosylationi66N-linked (GlcNAc...)Sequence analysis1
Glycosylationi74N-linked (GlcNAc...)Sequence analysis1
Glycosylationi116N-linked (GlcNAc...)Sequence analysis1
Glycosylationi126N-linked (GlcNAc...)Sequence analysis1
Glycosylationi149N-linked (GlcNAc...)Sequence analysis1
Glycosylationi155N-linked (GlcNAc...) (complex)1 Publication1

Post-translational modificationi

Glycosylated.2 Publications

Keywords - PTMi

Glycoprotein

Proteomic databases

EPDiQ8TCT8.
MaxQBiQ8TCT8.
PaxDbiQ8TCT8.
PeptideAtlasiQ8TCT8.
PRIDEiQ8TCT8.

PTM databases

iPTMnetiQ8TCT8.
PhosphoSitePlusiQ8TCT8.
SwissPalmiQ8TCT8.

Expressioni

Tissue specificityi

Ubiquitous.1 Publication

Gene expression databases

BgeeiENSG00000138600.
ExpressionAtlasiQ8TCT8. baseline and differential.
GenevisibleiQ8TCT8. HS.

Organism-specific databases

HPAiHPA036062.
HPA067304.

Interactioni

Subunit structurei

Interacts with ITM2B (PubMed:17965014).1 Publication

Binary interactionsi

WithEntry#Exp.IntActNotes
SGTAO437656EBI-750784,EBI-347996

GO - Molecular functioni

  • protein homodimerization activity Source: UniProtKB

Protein-protein interaction databases

BioGridi124328. 3 interactors.
IntActiQ8TCT8. 4 interactors.
MINTiMINT-1465822.
STRINGi9606.ENSP00000261854.

Structurei

3D structure databases

ProteinModelPortaliQ8TCT8.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini63 – 151PAAdd BLAST89

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi463 – 465PAL3
Motifi495 – 498YXXo lysosomal targeting motif4

Domaini

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; therefore, it is predicted to cleave type II-oriented substrate peptides like the prototypic protease SPP. The C-terminal tail is necessary for lysosomal transport.By similarity

Sequence similaritiesi

Belongs to the peptidase A22B family.Curated

Keywords - Domaini

Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG2442. Eukaryota.
ENOG410ZP52. LUCA.
GeneTreeiENSGT00530000062920.
HOGENOMiHOG000231496.
HOVERGENiHBG024193.
InParanoidiQ8TCT8.
KOiK09596.
OMAiCIMMVLL.
OrthoDBiEOG091G05NG.
PhylomeDBiQ8TCT8.
TreeFamiTF319186.

Family and domain databases

InterProiIPR003137. PA_domain.
IPR007369. Peptidase_A22B_SPP.
IPR006639. Preselin/SPP.
IPR033151. SPPL2a.
[Graphical view]
PANTHERiPTHR12174. PTHR12174. 1 hit.
PTHR12174:SF34. PTHR12174:SF34. 1 hit.
PfamiPF02225. PA. 1 hit.
PF04258. Peptidase_A22B. 1 hit.
[Graphical view]
SMARTiSM00730. PSN. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

Q8TCT8-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MGPQRRLSPA GAALLWGFLL QLTAAQEAIL HASGNGTTKD YCMLYNPYWT
60 70 80 90 100
ALPSTLENAT SISLMNLTST PLCNLSDIPP VGIKSKAVVV PWGSCHFLEK
110 120 130 140 150
ARIAQKGGAE AMLVVNNSVL FPPSGNRSEF PDVKILIAFI SYKDFRDMNQ
160 170 180 190 200
TLGDNITVKM YSPSWPNFDY TMVVIFVIAV FTVALGGYWS GLVELENLKA
210 220 230 240 250
VTTEDREMRK KKEEYLTFSP LTVVIFVVIC CVMMVLLYFF YKWLVYVMIA
260 270 280 290 300
IFCIASAMSL YNCLAALIHK IPYGQCTIAC RGKNMEVRLI FLSGLCIAVA
310 320 330 340 350
VVWAVFRNED RWAWILQDIL GIAFCLNLIK TLKLPNFKSC VILLGLLLLY
360 370 380 390 400
DVFFVFITPF ITKNGESIMV ELAAGPFGNN EKLPVVIRVP KLIYFSVMSV
410 420 430 440 450
CLMPVSILGF GDIIVPGLLI AYCRRFDVQT GSSYIYYVSS TVAYAIGMIL
460 470 480 490 500
TFVVLVLMKK GQPALLYLVP CTLITASVVA WRRKEMKKFW KGNSYQMMDH
510 520
LDCATNEENP VISGEQIVQQ
Length:520
Mass (Da):58,143
Last modified:November 8, 2002 - v2
Checksum:iA7A933A6504507DC
GO

Sequence cautioni

The sequence BAB55117 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated
The sequence CAD13133 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti126N → D in BAB55117 (PubMed:14702039).Curated1
Sequence conflicti271I → T in BAC11630 (PubMed:16303743).Curated1
Sequence conflicti406S → L in BAC11630 (PubMed:16303743).Curated1
Sequence conflicti446I → F in BAC11630 (PubMed:16303743).Curated1
Sequence conflicti511V → E in BAB55117 (PubMed:14702039).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_05179090V → I.Corresponds to variant rs8034443dbSNPEnsembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AJ345028 mRNA. Translation: CAC87789.1.
AY169314 mRNA. Translation: AAO12539.1.
AK027446 mRNA. Translation: BAB55117.1. Different initiation.
AK315651 mRNA. Translation: BAG38017.1.
AK075454 mRNA. Translation: BAC11630.1.
CH471082 Genomic DNA. Translation: EAW77410.1.
BC025740 mRNA. Translation: AAH25740.1.
AJ420896 mRNA. Translation: CAD13133.1. Different initiation.
CCDSiCCDS10138.1.
RefSeqiNP_116191.2. NM_032802.3.
UniGeneiHs.401537.

Genome annotation databases

EnsembliENST00000261854; ENSP00000261854; ENSG00000138600.
GeneIDi84888.
KEGGihsa:84888.
UCSCiuc001zyv.4. human.

Keywords - Coding sequence diversityi

Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AJ345028 mRNA. Translation: CAC87789.1.
AY169314 mRNA. Translation: AAO12539.1.
AK027446 mRNA. Translation: BAB55117.1. Different initiation.
AK315651 mRNA. Translation: BAG38017.1.
AK075454 mRNA. Translation: BAC11630.1.
CH471082 Genomic DNA. Translation: EAW77410.1.
BC025740 mRNA. Translation: AAH25740.1.
AJ420896 mRNA. Translation: CAD13133.1. Different initiation.
CCDSiCCDS10138.1.
RefSeqiNP_116191.2. NM_032802.3.
UniGeneiHs.401537.

3D structure databases

ProteinModelPortaliQ8TCT8.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi124328. 3 interactors.
IntActiQ8TCT8. 4 interactors.
MINTiMINT-1465822.
STRINGi9606.ENSP00000261854.

Protein family/group databases

MEROPSiA22.007.
TCDBi1.A.54.3.2. the presenilin er ca(2+) leak channel (presenilin) family.

PTM databases

iPTMnetiQ8TCT8.
PhosphoSitePlusiQ8TCT8.
SwissPalmiQ8TCT8.

Polymorphism and mutation databases

BioMutaiSPPL2A.
DMDMi25008981.

Proteomic databases

EPDiQ8TCT8.
MaxQBiQ8TCT8.
PaxDbiQ8TCT8.
PeptideAtlasiQ8TCT8.
PRIDEiQ8TCT8.

Protocols and materials databases

DNASUi84888.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000261854; ENSP00000261854; ENSG00000138600.
GeneIDi84888.
KEGGihsa:84888.
UCSCiuc001zyv.4. human.

Organism-specific databases

CTDi84888.
DisGeNETi84888.
GeneCardsiSPPL2A.
HGNCiHGNC:30227. SPPL2A.
HPAiHPA036062.
HPA067304.
MIMi608238. gene.
neXtProtiNX_Q8TCT8.
OpenTargetsiENSG00000138600.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG2442. Eukaryota.
ENOG410ZP52. LUCA.
GeneTreeiENSGT00530000062920.
HOGENOMiHOG000231496.
HOVERGENiHBG024193.
InParanoidiQ8TCT8.
KOiK09596.
OMAiCIMMVLL.
OrthoDBiEOG091G05NG.
PhylomeDBiQ8TCT8.
TreeFamiTF319186.

Enzyme and pathway databases

BioCyciZFISH:ENSG00000138600-MONOMER.
ReactomeiR-HSA-5357905. Regulation of TNFR1 signaling.

Miscellaneous databases

GeneWikiiSPPL2A.
GenomeRNAii84888.
PROiQ8TCT8.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000138600.
ExpressionAtlasiQ8TCT8. baseline and differential.
GenevisibleiQ8TCT8. HS.

Family and domain databases

InterProiIPR003137. PA_domain.
IPR007369. Peptidase_A22B_SPP.
IPR006639. Preselin/SPP.
IPR033151. SPPL2a.
[Graphical view]
PANTHERiPTHR12174. PTHR12174. 1 hit.
PTHR12174:SF34. PTHR12174:SF34. 1 hit.
PfamiPF02225. PA. 1 hit.
PF04258. Peptidase_A22B. 1 hit.
[Graphical view]
SMARTiSM00730. PSN. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiSPP2A_HUMAN
AccessioniPrimary (citable) accession number: Q8TCT8
Secondary accession number(s): B2RDS0, Q8TAW1, Q96SZ8
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 8, 2002
Last sequence update: November 8, 2002
Last modified: November 30, 2016
This is version 128 of the entry and version 2 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 15
    Human chromosome 15: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. Peptidase families
    Classification of peptidase families and list of entries
  6. 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.