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Q8TCT8 (SPP2A_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified March 19, 2014. Version 105. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Signal peptide peptidase-like 2A

Short name=SPP-like 2A
Short name=SPPL2a
EC=3.4.23.-
Alternative name(s):
Intramembrane protease 3
Short name=IMP-3
Presenilin-like protein 2
Gene names
Name:SPPL2A
Synonyms:IMP3, PSL2
ORF Names:PSEC0147
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length520 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. Ref.9 Ref.10 Ref.11 Ref.12

Subunit structure

Interacts with ITM2B. Ref.12

Subcellular location

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. Ref.9

Tissue specificity

Ubiquitous. Ref.8

Domain

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.

Post-translational modification

Glycosylated. Ref.8 Ref.13

Sequence similarities

Belongs to the peptidase A22B family.

Contains 1 PA (protease associated) domain.

Sequence caution

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.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 2525 Potential
Chain26 – 520495Signal peptide peptidase-like 2A
PRO_0000073910

Regions

Topological domain26 – 172147Lumenal Potential
Transmembrane173 – 19321Helical; Potential
Topological domain194 – 22027Cytoplasmic Potential
Transmembrane221 – 24121Helical; Potential
Topological domain242 – 2476Lumenal Potential
Transmembrane248 – 26821Helical; Potential
Topological domain269 – 28517Cytoplasmic Potential
Transmembrane286 – 30621Helical; Potential
Topological domain307 – 3115Lumenal Potential
Transmembrane312 – 33221Helical; Potential
Topological domain333 – 3408Cytoplasmic Potential
Transmembrane341 – 36121Helical; Potential
Topological domain362 – 39938Lumenal Potential
Transmembrane400 – 42021Helical; Potential
Topological domain421 – 43717Cytoplasmic Potential
Transmembrane438 – 45821Helical; Potential
Topological domain459 – 4602Lumenal Potential
Transmembrane461 – 48121Helical; Potential
Topological domain482 – 52039Cytoplasmic Potential
Domain63 – 15189PA
Motif463 – 4653PAL
Motif495 – 4984YXXo lysosomal targeting motif

Sites

Active site3511 By similarity
Active site4121 By similarity

Amino acid modifications

Glycosylation581N-linked (GlcNAc...) Potential
Glycosylation661N-linked (GlcNAc...) Potential
Glycosylation741N-linked (GlcNAc...) Potential
Glycosylation1161N-linked (GlcNAc...) Potential
Glycosylation1261N-linked (GlcNAc...) Potential
Glycosylation1491N-linked (GlcNAc...) Potential
Glycosylation1551N-linked (GlcNAc...) (complex) Ref.13

Natural variations

Natural variant901V → I.
Corresponds to variant rs8034443 [ dbSNP | Ensembl ].
VAR_051790

Experimental info

Mutagenesis4121D → A: Loss of intramembrane-cleaving activity toward FASLG, ITM2B and TNF. Ref.9 Ref.11 Ref.12
Sequence conflict1261N → D in BAB55117. Ref.3
Sequence conflict2711I → T in BAC11630. Ref.4
Sequence conflict4061S → L in BAC11630. Ref.4
Sequence conflict4461I → F in BAC11630. Ref.4
Sequence conflict5111V → E in BAB55117. Ref.3

Sequences

Sequence LengthMass (Da)Tools
Q8TCT8 [UniParc].

Last modified November 8, 2002. Version 2.
Checksum: A7A933A6504507DC

FASTA52058,143
        10         20         30         40         50         60 
MGPQRRLSPA GAALLWGFLL QLTAAQEAIL HASGNGTTKD YCMLYNPYWT ALPSTLENAT 

        70         80         90        100        110        120 
SISLMNLTST PLCNLSDIPP VGIKSKAVVV PWGSCHFLEK ARIAQKGGAE AMLVVNNSVL 

       130        140        150        160        170        180 
FPPSGNRSEF PDVKILIAFI SYKDFRDMNQ TLGDNITVKM YSPSWPNFDY TMVVIFVIAV 

       190        200        210        220        230        240 
FTVALGGYWS GLVELENLKA VTTEDREMRK KKEEYLTFSP LTVVIFVVIC CVMMVLLYFF 

       250        260        270        280        290        300 
YKWLVYVMIA IFCIASAMSL YNCLAALIHK IPYGQCTIAC RGKNMEVRLI FLSGLCIAVA 

       310        320        330        340        350        360 
VVWAVFRNED RWAWILQDIL GIAFCLNLIK TLKLPNFKSC VILLGLLLLY DVFFVFITPF 

       370        380        390        400        410        420 
ITKNGESIMV ELAAGPFGNN EKLPVVIRVP KLIYFSVMSV CLMPVSILGF GDIIVPGLLI 

       430        440        450        460        470        480 
AYCRRFDVQT GSSYIYYVSS TVAYAIGMIL TFVVLVLMKK GQPALLYLVP CTLITASVVA 

       490        500        510        520 
WRRKEMKKFW KGNSYQMMDH LDCATNEENP VISGEQIVQQ 

« Hide

References

« Hide 'large scale' references
[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. expand/collapse author list , 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. expand/collapse author list , 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]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases
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]"The Fas ligand intracellular domain is released by ADAM10 and SPPL2a cleavage in T-cells."
Kirkin V., Cahuzac N., Guardiola-Serrano F., Huault S., Luckerath K., Friedmann E., Novac N., Wels W.S., Martoglio B., Hueber A.O., Zornig M.
Cell Death Differ. 14:1678-1687(2007) [PubMed] [Europe PMC] [Abstract]
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]"A strategy for precise and large scale identification of core fucosylated glycoproteins."
Jia W., Lu Z., Fu Y., Wang H.P., Wang L.H., Chi H., Yuan Z.F., Zheng Z.B., Song L.N., Han H.H., Liang Y.M., Wang J.L., Cai Y., Zhang Y.K., Deng Y.L., Ying W.T., He S.M., Qian X.H.
Mol. Cell. Proteomics 8:913-923(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: GLYCOSYLATION AT ASN-155.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
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.
RefSeqNP_116191.2. NM_032802.3.
UniGeneHs.401537.

3D structure databases

ProteinModelPortalQ8TCT8.
SMRQ8TCT8. Positions 80-161.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid124328. 2 interactions.
IntActQ8TCT8. 4 interactions.
MINTMINT-1465822.

Protein family/group databases

MEROPSA22.007.
TCDB1.A.54.3.2. the presenilin er ca(2+) leak channel (presenilin) family.

PTM databases

PhosphoSiteQ8TCT8.

Polymorphism databases

DMDM25008981.

Proteomic databases

PaxDbQ8TCT8.
PeptideAtlasQ8TCT8.
PRIDEQ8TCT8.

Protocols and materials databases

DNASU84888.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000261854; ENSP00000261854; ENSG00000138600.
GeneID84888.
KEGGhsa:84888.
UCSCuc001zyv.3. human.

Organism-specific databases

CTD84888.
GeneCardsGC15M050999.
HGNCHGNC:30227. SPPL2A.
HPAHPA036062.
MIM608238. gene.
neXtProtNX_Q8TCT8.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG250196.
HOGENOMHOG000231496.
HOVERGENHBG024193.
InParanoidQ8TCT8.
KOK09596.
OMASDIPPDG.
OrthoDBEOG769ZJ4.
PhylomeDBQ8TCT8.
TreeFamTF319186.

Gene expression databases

ArrayExpressQ8TCT8.
BgeeQ8TCT8.
GenevestigatorQ8TCT8.

Family and domain databases

InterProIPR007369. Peptidase_A22B_SPP.
IPR006639. Preselin/SPP.
IPR003137. Protease-assoc_domain.
[Graphical view]
PANTHERPTHR12174. PTHR12174. 1 hit.
PfamPF02225. PA. 1 hit.
PF04258. Peptidase_A22B. 1 hit.
[Graphical view]
SMARTSM00730. PSN. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

GeneWikiSPPL2A.
GenomeRNAi84888.
NextBio75209.
PROQ8TCT8.
SOURCESearch...

Entry information

Entry nameSPP2A_HUMAN
AccessionPrimary (citable) accession number: Q8TCT8
Secondary accession number(s): B2RDS0, Q8TAW1, Q96SZ8
Entry history
Integrated into UniProtKB/Swiss-Prot: November 8, 2002
Last sequence update: November 8, 2002
Last modified: March 19, 2014
This is version 105 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

Peptidase families

Classification of peptidase families and list of entries

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 15

Human chromosome 15: entries, gene names and cross-references to MIM