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Q8TCT8

- SPP2A_HUMAN

UniProt

Q8TCT8 - SPP2A_HUMAN

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Protein
Signal peptide peptidase-like 2A
Gene
SPPL2A, IMP3, PSL2, PSEC0147
Organism
Homo sapiens (Human)
Status
Reviewed - 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. 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. Also responsible for the intramembrane cleavage of Fas antigen ligand FASLG, which promotes the release of the intracellular FasL domain (FasL ICD). May play a role in the regulation of innate and adaptive immunity.4 Publications

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Active sitei351 – 3511 By similarity
Active sitei412 – 4121 By similarity

GO - Molecular functioni

  1. aspartic-type endopeptidase activity Source: InterPro
  2. protein binding Source: UniProtKB
  3. protein homodimerization activity Source: UniProtKB

GO - Biological processi

  1. membrane protein ectodomain proteolysis Source: UniProtKB
  2. membrane protein intracellular domain proteolysis Source: UniProtKB
  3. regulation of immune response Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Hydrolase, Protease

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 2A (EC:3.4.23.-)
Short name:
SPP-like 2A
Short name:
SPPL2a
Alternative name(s):
Intramembrane protease 3
Short name:
IMP-3
Presenilin-like protein 2
Gene namesi
Name:SPPL2A
Synonyms:IMP3, PSL2
ORF Names:PSEC0147
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640: Chromosome 15

Organism-specific databases

HGNCiHGNC:30227. SPPL2A.

Subcellular locationi

Late endosome membrane; Multi-pass membrane protein By similarity. Lysosome membrane; Multi-pass membrane protein By similarity. Cell membrane
Note: Colocalizes with palmitoylated and myristoylated proteins at the plasma membrane.1 Publication

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini26 – 172147Lumenal Reviewed prediction
Add
BLAST
Transmembranei173 – 19321Helical; Reviewed prediction
Add
BLAST
Topological domaini194 – 22027Cytoplasmic Reviewed prediction
Add
BLAST
Transmembranei221 – 24121Helical; Reviewed prediction
Add
BLAST
Topological domaini242 – 2476Lumenal Reviewed prediction
Transmembranei248 – 26821Helical; Reviewed prediction
Add
BLAST
Topological domaini269 – 28517Cytoplasmic Reviewed prediction
Add
BLAST
Transmembranei286 – 30621Helical; Reviewed prediction
Add
BLAST
Topological domaini307 – 3115Lumenal Reviewed prediction
Transmembranei312 – 33221Helical; Reviewed prediction
Add
BLAST
Topological domaini333 – 3408Cytoplasmic Reviewed prediction
Transmembranei341 – 36121Helical; Reviewed prediction
Add
BLAST
Topological domaini362 – 39938Lumenal Reviewed prediction
Add
BLAST
Transmembranei400 – 42021Helical; Reviewed prediction
Add
BLAST
Topological domaini421 – 43717Cytoplasmic Reviewed prediction
Add
BLAST
Transmembranei438 – 45821Helical; Reviewed prediction
Add
BLAST
Topological domaini459 – 4602Lumenal Reviewed prediction
Transmembranei461 – 48121Helical; Reviewed prediction
Add
BLAST
Topological domaini482 – 52039Cytoplasmic Reviewed prediction
Add
BLAST

GO - Cellular componenti

  1. Golgi-associated vesicle membrane Source: UniProtKB
  2. integral component of cytoplasmic side of endoplasmic reticulum membrane Source: UniProtKB
  3. integral component of lumenal side of endoplasmic reticulum membrane Source: UniProtKB
  4. late endosome membrane Source: UniProtKB-SubCell
  5. lysosomal membrane Source: UniProtKB
  6. plasma membrane Source: UniProtKB-SubCell
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Endosome, Lysosome, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi412 – 4121D → A: Loss of intramembrane-cleaving activity toward FASLG, ITM2B and TNF. 3 Publications

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Signal peptidei1 – 2525 Reviewed prediction
Add
BLAST
Chaini26 – 520495Signal peptide peptidase-like 2A
PRO_0000073910Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Glycosylationi58 – 581N-linked (GlcNAc...) Reviewed prediction
Glycosylationi66 – 661N-linked (GlcNAc...) Reviewed prediction
Glycosylationi74 – 741N-linked (GlcNAc...) Reviewed prediction
Glycosylationi116 – 1161N-linked (GlcNAc...) Reviewed prediction
Glycosylationi126 – 1261N-linked (GlcNAc...) Reviewed prediction
Glycosylationi149 – 1491N-linked (GlcNAc...) Reviewed prediction
Glycosylationi155 – 1551N-linked (GlcNAc...) (complex)1 Publication

Post-translational modificationi

Glycosylated.2 Publications

Keywords - PTMi

Glycoprotein

Proteomic databases

MaxQBiQ8TCT8.
PaxDbiQ8TCT8.
PeptideAtlasiQ8TCT8.
PRIDEiQ8TCT8.

PTM databases

PhosphoSiteiQ8TCT8.

Expressioni

Tissue specificityi

Ubiquitous.1 Publication

Gene expression databases

ArrayExpressiQ8TCT8.
BgeeiQ8TCT8.
GenevestigatoriQ8TCT8.

Organism-specific databases

HPAiHPA036062.

Interactioni

Subunit structurei

Interacts with ITM2B.1 Publication

Protein-protein interaction databases

BioGridi124328. 2 interactions.
IntActiQ8TCT8. 4 interactions.
MINTiMINT-1465822.

Structurei

3D structure databases

ProteinModelPortaliQ8TCT8.
SMRiQ8TCT8. Positions 80-161.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini63 – 15189PA
Add
BLAST

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi463 – 4653PAL
Motifi495 – 4984YXXo lysosomal targeting motif

Domaini

The PAL motif is required for normal active site conformation By similarity. 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.

Sequence similaritiesi

Belongs to the peptidase A22B family.

Keywords - Domaini

Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiNOG250196.
HOGENOMiHOG000231496.
HOVERGENiHBG024193.
InParanoidiQ8TCT8.
KOiK09596.
OMAiSCTIAYA.
OrthoDBiEOG769ZJ4.
PhylomeDBiQ8TCT8.
TreeFamiTF319186.

Family and domain databases

InterProiIPR007369. Peptidase_A22B_SPP.
IPR006639. Preselin/SPP.
IPR003137. Protease-assoc_domain.
[Graphical view]
PANTHERiPTHR12174. PTHR12174. 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

MGPQRRLSPA GAALLWGFLL QLTAAQEAIL HASGNGTTKD YCMLYNPYWT    50
ALPSTLENAT SISLMNLTST PLCNLSDIPP VGIKSKAVVV PWGSCHFLEK 100
ARIAQKGGAE AMLVVNNSVL FPPSGNRSEF PDVKILIAFI SYKDFRDMNQ 150
TLGDNITVKM YSPSWPNFDY TMVVIFVIAV FTVALGGYWS GLVELENLKA 200
VTTEDREMRK KKEEYLTFSP LTVVIFVVIC CVMMVLLYFF YKWLVYVMIA 250
IFCIASAMSL YNCLAALIHK IPYGQCTIAC RGKNMEVRLI FLSGLCIAVA 300
VVWAVFRNED RWAWILQDIL GIAFCLNLIK TLKLPNFKSC VILLGLLLLY 350
DVFFVFITPF ITKNGESIMV ELAAGPFGNN EKLPVVIRVP KLIYFSVMSV 400
CLMPVSILGF GDIIVPGLLI AYCRRFDVQT GSSYIYYVSS TVAYAIGMIL 450
TFVVLVLMKK GQPALLYLVP CTLITASVVA WRRKEMKKFW KGNSYQMMDH 500
LDCATNEENP VISGEQIVQQ 520
Length:520
Mass (Da):58,143
Last modified:November 8, 2002 - v2
Checksum:iA7A933A6504507DC
GO

Sequence cautioni

The sequence BAB55117.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.
The sequence CAD13133.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti90 – 901V → I.
Corresponds to variant rs8034443 [ dbSNP | Ensembl ].
VAR_051790

Sequence conflict

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti126 – 1261N → D in BAB55117. 1 Publication
Sequence conflicti271 – 2711I → T in BAC11630. 1 Publication
Sequence conflicti406 – 4061S → L in BAC11630. 1 Publication
Sequence conflicti446 – 4461I → F in BAC11630. 1 Publication
Sequence conflicti511 – 5111V → E in BAB55117. 1 Publication

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
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.3. human.

Polymorphism databases

DMDMi25008981.

Keywords - Coding sequence diversityi

Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
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.
CCDSi CCDS10138.1.
RefSeqi NP_116191.2. NM_032802.3.
UniGenei Hs.401537.

3D structure databases

ProteinModelPortali Q8TCT8.
SMRi Q8TCT8. Positions 80-161.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 124328. 2 interactions.
IntActi Q8TCT8. 4 interactions.
MINTi MINT-1465822.

Protein family/group databases

MEROPSi A22.007.
TCDBi 1.A.54.3.2. the presenilin er ca(2+) leak channel (presenilin) family.

PTM databases

PhosphoSitei Q8TCT8.

Polymorphism databases

DMDMi 25008981.

Proteomic databases

MaxQBi Q8TCT8.
PaxDbi Q8TCT8.
PeptideAtlasi Q8TCT8.
PRIDEi Q8TCT8.

Protocols and materials databases

DNASUi 84888.
Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENST00000261854 ; ENSP00000261854 ; ENSG00000138600 .
GeneIDi 84888.
KEGGi hsa:84888.
UCSCi uc001zyv.3. human.

Organism-specific databases

CTDi 84888.
GeneCardsi GC15M050999.
HGNCi HGNC:30227. SPPL2A.
HPAi HPA036062.
MIMi 608238. gene.
neXtProti NX_Q8TCT8.
GenAtlasi Search...

Phylogenomic databases

eggNOGi NOG250196.
HOGENOMi HOG000231496.
HOVERGENi HBG024193.
InParanoidi Q8TCT8.
KOi K09596.
OMAi SCTIAYA.
OrthoDBi EOG769ZJ4.
PhylomeDBi Q8TCT8.
TreeFami TF319186.

Miscellaneous databases

GeneWikii SPPL2A.
GenomeRNAii 84888.
NextBioi 75209.
PROi Q8TCT8.
SOURCEi Search...

Gene expression databases

ArrayExpressi Q8TCT8.
Bgeei Q8TCT8.
Genevestigatori Q8TCT8.

Family and domain databases

InterProi IPR007369. Peptidase_A22B_SPP.
IPR006639. Preselin/SPP.
IPR003137. Protease-assoc_domain.
[Graphical view ]
PANTHERi PTHR12174. PTHR12174. 1 hit.
Pfami PF02225. PA. 1 hit.
PF04258. Peptidase_A22B. 1 hit.
[Graphical view ]
SMARTi SM00730. PSN. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  1. "Characterization of a new protein family with homology to presenilins."
    Irmler M., Tomiuk S., Korner M.R., Hofmann K., Conradt M.
    Submitted (SEP-2001) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [MRNA].
  2. "Novel class of polytopic proteins with domains associated with putative protease activity."
    Grigorenko A.P., Moliaka Y.K., Korovaitseva G.I., Rogaev E.I.
    Biochemistry (Mosc.) 67:826-834(2002) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA].
    Tissue: Blood.
  3. "Complete sequencing and characterization of 21,243 full-length human cDNAs."
    Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.
    , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
    Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Tissue: Synovium and Teratocarcinoma.
  4. "Signal sequence and keyword trap in silico for selection of full-length human cDNAs encoding secretion or membrane proteins from oligo-capped cDNA libraries."
    Otsuki T., Ota T., Nishikawa T., Hayashi K., Suzuki Y., Yamamoto J., Wakamatsu A., Kimura K., Sakamoto K., Hatano N., Kawai Y., Ishii S., Saito K., Kojima S., Sugiyama T., Ono T., Okano K., Yoshikawa Y.
    , Aotsuka S., Sasaki N., Hattori A., Okumura K., Nagai K., Sugano S., Isogai T.
    DNA Res. 12:117-126(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Tissue: Placenta.
  5. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  6. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Tissue: Pancreas.
  7. "Identification of signal peptide peptidase, a presenilin-type aspartic protease."
    Weihofen A., Binns K., Lemberg M.K., Ashman K., Martoglio B.
    Science 296:2215-2218(2002) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 91-520.
    Tissue: Cervix carcinoma.
  8. "Consensus analysis of signal peptide peptidase and homologous human aspartic proteases reveals opposite topology of catalytic domains compared with presenilins."
    Friedmann E., Lemberg M.K., Weihofen A., Dev K.K., Dengler U., Rovelli G., Martoglio B.
    J. Biol. Chem. 279:50790-50798(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: GLYCOSYLATION, TOPOLOGY, TISSUE SPECIFICITY.
  9. "SPPL2a and SPPL2b promote intramembrane proteolysis of TNFalpha in activated dendritic cells to trigger IL-12 production."
    Friedmann E., Hauben E., Maylandt K., Schleeger S., Vreugde S., Lichtenthaler S.F., Kuhn P.H., Stauffer D., Rovelli G., Martoglio B.
    Nat. Cell Biol. 8:843-848(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN CLEAVAGE OF TNF, SUBCELLULAR LOCATION, MUTAGENESIS OF ASP-412.
  10. "A gamma-secretase-like intramembrane cleavage of TNFalpha by the GxGD aspartyl protease SPPL2b."
    Fluhrer R., Grammer G., Israel L., Condron M.M., Haffner C., Friedmann E., Bohland C., Imhof A., Martoglio B., Teplow D.B., Haass C.
    Nat. Cell Biol. 8:894-896(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN CLEAVAGE OF TNF.
  11. Cited for: FUNCTION IN CLEAVAGE OF FASLG, MUTAGENESIS OF ASP-412.
  12. "Regulated intramembrane proteolysis of Bri2 (Itm2b) by ADAM10 and SPPL2a/SPPL2b."
    Martin L., Fluhrer R., Reiss K., Kremmer E., Saftig P., Haass C.
    J. Biol. Chem. 283:1644-1652(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN CLEAVAGE OF ITM2B, INTERACTION WITH ITM2B, MUTAGENESIS OF ASP-412.
  13. Cited for: GLYCOSYLATION AT ASN-155.

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: July 9, 2014
This is version 108 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

External Data

Dasty 3

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