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Q8TCT7 (SPP2B_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 115. 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·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Signal peptide peptidase-like 2B

Short name=SPP-like 2B
Short name=SPPL2b
EC=3.4.23.-
Alternative name(s):
Intramembrane protease 4
Short name=IMP-4
Presenilin homologous protein 4
Short name=PSH4
Presenilin-like protein 1
Gene names
Name:SPPL2B
Synonyms:IMP4, KIAA1532, PSL1
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length592 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 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. May play a role in the regulation of innate and adaptive immunity. Ref.12 Ref.13 Ref.14 Ref.15 Ref.16

Subunit structure

Monomer. Homodimer. Interacts with ITM2B and TNF. Ref.11 Ref.13 Ref.14

Subcellular location

Golgi apparatus membrane; Multi-pass membrane protein. Note: targeted through the entire secretory pathway to endosomes/lysosomes. Ref.10 Ref.14

Tissue specificity

Expressed predominantly in adrenal cortex and mammary gland. Ref.9

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.9 Ref.10

Sequence similarities

Belongs to the peptidase A22B family.

Contains 1 PA (protease associated) domain.

Sequence caution

The sequence AAC05601.1 differs from that shown. Reason: Erroneous gene model prediction.

The sequence AAG45441.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.

The sequence BAA96056.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.

Alternative products

This entry describes 4 isoforms produced by alternative splicing. [Align] [Select]

Note: Experimental confirmation may be lacking for some isoforms.
Isoform 1 (identifier: Q8TCT7-1)

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.
Isoform 2 (identifier: Q8TCT7-2)

The sequence of this isoform differs from the canonical sequence as follows:
     320-592: Missing.
Isoform 3 (identifier: Q8TCT7-3)

The sequence of this isoform differs from the canonical sequence as follows:
     280-291: Missing.
     320-592: Missing.
Isoform 4 (identifier: Q8TCT7-4)

The sequence of this isoform differs from the canonical sequence as follows:
     506-511: KVLPPS → VNTSLL
     512-592: Missing.
Note: No experimental confirmation available.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 2525 Potential
Chain26 – 592567Signal peptide peptidase-like 2B
PRO_0000073909

Regions

Topological domain26 – 174149Lumenal Potential
Transmembrane175 – 19521Helical; Potential
Topological domain196 – 22126Cytoplasmic Potential
Transmembrane222 – 24423Helical; Potential
Topological domain245 – 2484Lumenal Potential
Transmembrane249 – 27123Helical; Potential
Topological domain272 – 29322Cytoplasmic Potential
Transmembrane294 – 31421Helical; Potential
Topological domain315 – 3195Lumenal Potential
Transmembrane320 – 34021Helical; Potential
Topological domain341 – 3488Cytoplasmic Potential
Transmembrane349 – 36921Helical; Potential
Topological domain370 – 41243Lumenal Potential
Transmembrane413 – 43321Helical; Potential
Topological domain434 – 44512Cytoplasmic Potential
Transmembrane446 – 46621Helical; Potential
Topological domain467 – 4704Lumenal Potential
Transmembrane471 – 49121Helical; Potential
Topological domain492 – 592101Cytoplasmic Potential
Domain71 – 14979PA
Motif472 – 4743PAL
Compositional bias350 – 3578Poly-Leu
Compositional bias509 – 55143Pro-rich

Sites

Active site3591 By similarity
Active site4211 By similarity

Amino acid modifications

Glycosylation971N-linked (GlcNAc...) Potential
Glycosylation1291N-linked (GlcNAc...) Potential

Natural variations

Alternative sequence280 – 29112Missing in isoform 3.
VSP_005203
Alternative sequence320 – 592273Missing in isoform 2 and isoform 3.
VSP_005204
Alternative sequence506 – 5116KVLPPS → VNTSLL in isoform 4.
VSP_009221
Alternative sequence512 – 59281Missing in isoform 4.
VSP_009222
Natural variant5741S → P.
Corresponds to variant rs10402284 [ dbSNP | Ensembl ].
VAR_059780

Experimental info

Mutagenesis4211D → A: Loss of intramembrane-cleaving activity toward ITM2B and TNF. Ref.13 Ref.14 Ref.15 Ref.16

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified May 16, 2006. Version 2.
Checksum: 0F49370F16D36AA0

FASTA59264,644
        10         20         30         40         50         60 
MAAAVAAALA RLLAAFLLLA AQVACEYGMV HVVSQAGGPE GKDYCILYNP QWAHLPHDLS 

        70         80         90        100        110        120 
KASFLQLRNW TASLLCSAAD LPARGFSNQI PLVARGNCTF YEKVRLAQGS GARGLLIVSR 

       130        140        150        160        170        180 
ERLVPPGGNK TQYDEIGIPV ALLSYKDMLD IFTRFGRTVR AALYAPKEPV LDYNMVIIFI 

       190        200        210        220        230        240 
MAVGTVAIGG YWAGSRDVKK RYMKHKRDDG PEKQEDEAVD VTPVMTCVFV VMCCSMLVLL 

       250        260        270        280        290        300 
YYFYDLLVYV VIGIFCLASA TGLYSCLAPC VRRLPFGKCR IPNNSLPYFH KRPQARMLLL 

       310        320        330        340        350        360 
ALFCVAVSVV WGVFRNEDQW AWVLQDALGI AFCLYMLKTI RLPTFKACTL LLLVLFLYDI 

       370        380        390        400        410        420 
FFVFITPFLT KSGSSIMVEV ATGPSDSATR EKLPMVLKVP RLNSSPLALC DRPFSLLGFG 

       430        440        450        460        470        480 
DILVPGLLVA YCHRFDIQVQ SSRVYFVACT IAYGVGLLVT FVALALMQRG QPALLYLVPC 

       490        500        510        520        530        540 
TLVTSCAVAL WRRELGVFWT GSGFAKVLPP SPWAPAPADG PQPPKDSATP LSPQPPSEEP 

       550        560        570        580        590 
ATSPWPAEQS PKSRTSEEMG AGAPMREPGS PAESEGRDQA QPSPVTQPGA SA 

« Hide

Isoform 2 [UniParc].

Checksum: 5EFEEB110C4C7D7B
Show »

FASTA31935,295
Isoform 3 [UniParc].

Checksum: 4AFCE5838F23543F
Show »

FASTA30733,827
Isoform 4 [UniParc].

Checksum: 6B496A9879E9D57F
Show »

FASTA51156,431

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] (ISOFORM 1).
[2]Martoglio B.
Submitted (NOV-2001) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[3]"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] (ISOFORM 1).
Tissue: Blood.
[4]"Prediction of the coding sequences of unidentified human genes. XVII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro."
Nagase T., Kikuno R., Ishikawa K., Hirosawa M., Ohara O.
DNA Res. 7:143-150(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
Tissue: Brain.
[5]"The DNA sequence and biology of human chromosome 19."
Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S., Carrano A.V. expand/collapse author list , Caoile C., Chan Y.M., Christensen M., Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E., Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M., Rubin E.M., Lucas S.M.
Nature 428:529-535(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]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 (SEP-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]"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] (ISOFORMS 1; 2 AND 4).
Tissue: Brain, Eye and Testis.
[8]The European IMAGE consortium
Submitted (JUL-2000) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 201-318 (ISOFORM 3).
[9]"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.
[10]"Differential localization and identification of a critical aspartate suggest non-redundant proteolytic functions of the presenilin homologues SPPL2b and SPPL3."
Krawitz P., Haffner C., Fluhrer R., Steiner H., Schmid B., Haass C.
J. Biol. Chem. 280:39515-39523(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: GLYCOSYLATION, SUBCELLULAR LOCATION.
[11]"Intramembrane proteolytic cleavage by human signal peptide peptidase like 3 and malaria signal peptide peptidase."
Nyborg A.C., Ladd T.B., Jansen K., Kukar T., Golde T.E.
FASEB J. 20:1671-1679(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: HOMODIMERIZATION.
[12]"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.
[13]"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, INTERACTION WITH TNF, MUTAGENESIS OF ASP-421.
[14]"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, SUBCELLULAR LOCATION, INTERACTION WITH ITM2B, MUTAGENESIS OF ASP-421.
[15]"Substrate requirements for SPPL2b-dependent regulated intramembrane proteolysis."
Martin L., Fluhrer R., Haass C.
J. Biol. Chem. 284:5662-5670(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN CLEAVAGE OF ITM2B, MUTAGENESIS OF ASP-421.
[16]"The alpha-helical content of the transmembrane domain of the British dementia protein-2 (Bri2) determines its processing by signal peptide peptidase-like 2b (SPPL2b)."
Fluhrer R., Martin L., Klier B., Haug-Kroper M., Grammer G., Nuscher B., Haass C.
J. Biol. Chem. 287:5156-5163(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN CLEAVAGE OF ITM2B, MUTAGENESIS OF ASP-421.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AJ345027 mRNA. Translation: CAC87788.1.
AJ420897 mRNA. Translation: CAD13134.1.
AY169315 mRNA. Translation: AAO12540.1.
AB040965 mRNA. Translation: BAA96056.1. Different initiation.
AC004410 Genomic DNA. Translation: AAC05601.1. Sequence problems.
AC005258 Genomic DNA. Translation: AAG45441.1. Different initiation.
CH471139 Genomic DNA. Translation: EAW69383.1.
CH471139 Genomic DNA. Translation: EAW69388.1.
BC001788 mRNA. Translation: AAH01788.2.
BC028391 mRNA. Translation: AAH28391.2.
BC093046 mRNA. Translation: AAH93046.1.
AL365405 mRNA. Translation: CAB96951.1. Sequence problems.
RefSeqNP_001070706.1. NM_001077238.1.
NP_694533.1. NM_152988.2.
UniGeneHs.744026.

3D structure databases

ProteinModelPortalQ8TCT7.
SMRQ8TCT7. Positions 82-159.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid121255. 1 interaction.
IntActQ8TCT7. 2 interactions.

Protein family/group databases

MEROPSA22.004.

PTM databases

PhosphoSiteQ8TCT7.

Polymorphism databases

DMDM97537015.

Proteomic databases

PaxDbQ8TCT7.
PRIDEQ8TCT7.

Protocols and materials databases

DNASU56928.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

GeneID56928.
KEGGhsa:56928.
UCSCuc002lvr.3. human. [Q8TCT7-4]
uc002lvs.3. human. [Q8TCT7-1]

Organism-specific databases

CTD56928.
GeneCardsGC19P002328.
H-InvDBHIX0158528.
HGNCHGNC:30627. SPPL2B.
MIM608239. gene.
neXtProtNX_Q8TCT7.
HUGESearch...
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG250196.
HOVERGENHBG024193.
InParanoidQ8TCT7.
KOK09597.
PhylomeDBQ8TCT7.

Gene expression databases

GenevestigatorQ8TCT7.

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

ChiTaRSSPPL2B. human.
GeneWikiSPPL2B.
GenomeRNAi56928.
NextBio62462.
PROQ8TCT7.
SOURCESearch...

Entry information

Entry nameSPP2B_HUMAN
AccessionPrimary (citable) accession number: Q8TCT7
Secondary accession number(s): D6W609 expand/collapse secondary AC list , O60365, Q567S3, Q8IUH9, Q9BUY6, Q9H3M4, Q9NPN2, Q9P1Z6
Entry history
Integrated into UniProtKB/Swiss-Prot: November 8, 2002
Last sequence update: May 16, 2006
Last modified: April 16, 2014
This is version 115 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 19

Human chromosome 19: entries, gene names and cross-references to MIM