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O43462 (MBTP2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 124. 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:
Membrane-bound transcription factor site-2 protease

EC=3.4.24.85
Alternative name(s):
Endopeptidase S2P
Sterol regulatory element-binding proteins intramembrane protease
Short name=SREBPs intramembrane protease
Gene names
Name:MBTPS2
Synonyms:S2P
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length519 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Intramembrane proteolysis of sterol-regulatory element-binding proteins (SREBPs) within the first transmembrane segment thereby releasing the N-terminal segment with a portion of the transmembrane segment attached. Site-2 cleavage comes after site-1 cleavage which takes place in the lumenal loop.

Catalytic activity

Cleaves several transcription factors that are type-2 transmembrane proteins within membrane-spanning domains. Known substrates include sterol regulatory element-binding protein (SREBP) -1, SREBP-2 and forms of the transcriptional activator ATF6. SREBP-2 is cleaved at the site 477-DRSRILL-|-CVLTFLCLSFNPLTSLLQWGGA-505. The residues Asn-Pro, 11 residues distal to the site of cleavage in the membrane-spanning domain, are important for cleavage by S2P endopeptidase. Replacement of either of these residues does not prevent cleavage, but there is no cleavage if both of these residues are replaced.

Cofactor

Binds 1 zinc ion per subunit.

Subcellular location

Membrane; Multi-pass membrane protein Probable. Cytoplasm Ref.5.

Tissue specificity

Expressed in heart, brain, placenta, lung, liver, muscle, kidney and pancreas.

Involvement in disease

IFAP syndrome with or without BRESHECK syndrome (IFAPS) [MIM:308205]: A syndrome characterized by a peculiar triad of follicular ichthyosis, total or subtotal atrichia, and photophobia of varying degree. Histopathologically, the epidermal granular layer is generally well-preserved or thickened at the infundibulum. Hair follicles are poorly developed and tend to be surrounded by an inflammatory infiltrate. A subgroup of patients is described with lamellar rather than follicular ichthyosis. Non-consistent features may include growth and psychomotor retardation, aganglionic megacolon, seizures and nail dystrophy.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.5

Keratosis follicularis spinulosa decalvans X-linked (KFSDX) [MIM:308800]: A rare disorder affecting the skin and the eye. Affected men show thickening of the skin of the neck, ears, and extremities, especially the palms and soles, loss of eyebrows, eyelashes and beard, thickening of the eyelids with blepharitis and ectropion, and corneal degeneration.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.6

Sequence similarities

Belongs to the peptidase M50A family.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 519519Membrane-bound transcription factor site-2 protease
PRO_0000088482

Regions

Topological domain1 – 33Cytoplasmic Ref.3
Transmembrane4 – 2421Helical; Potential
Topological domain25 – 7450Lumenal Probable
Transmembrane75 – 9521Helical; Potential
Transmembrane96 – 10712Helical; Potential
Topological domain108 – 14437Lumenal Probable
Transmembrane145 – 16925Helical; Potential
Transmembrane174 – 18613Helical; Potential
Transmembrane187 – 20923Helical; Potential
Transmembrane229 – 25123Helical; Potential
Topological domain252 – 446195Lumenal Probable
Transmembrane447 – 46418Helical; Potential
Transmembrane465 – 47612Helical; Potential
Topological domain477 – 49216Lumenal Potential
Transmembrane493 – 51321Helical; Potential
Topological domain514 – 5196Cytoplasmic Potential
Compositional bias109 – 13628Poly-Ser
Compositional bias285 – 386102Cys-rich
Compositional bias380 – 3845Poly-Ser

Sites

Active site1721
Metal binding1711Zinc; catalytic
Metal binding1751Zinc; catalytic

Amino acid modifications

Glycosylation3371N-linked (GlcNAc...) Ref.3

Natural variations

Natural variant871M → I in IFAPS; does not affect subcellular localization; impairs activity. Ref.5
VAR_063054
Natural variant2261W → L in IFAPS; does not affect subcellular localization; impairs activity. Ref.5
VAR_063055
Natural variant2271H → L in IFAPS; does not affect subcellular localization; impairs activity. Ref.5
VAR_063056
Natural variant4291R → H in IFAPS; does not affect subcellular localization; impairs activity. Ref.5
VAR_063057
Natural variant4751F → S in IFAPS; does not affect subcellular localization; impairs activity. Ref.5
VAR_063058
Natural variant5081N → S in KFSDX; sterol responsiveness is reduced by half. Ref.6
VAR_064409

Experimental info

Mutagenesis1711H → F: Loss of activity. Ref.1
Mutagenesis1721E → A or Q: Loss of activity. Ref.1
Mutagenesis1721E → D: Partial loss of activity. Ref.1
Mutagenesis1751H → F: Loss of activity. Ref.1
Mutagenesis4671D → N: Loss of activity. Ref.1

Sequences

Sequence LengthMass (Da)Tools
O43462 [UniParc].

Last modified June 1, 1998. Version 1.
Checksum: 247D69E0FD7747BD

FASTA51957,444
        10         20         30         40         50         60 
MIPVSLVVVV VGGWTVVYLT DLVLKSSVYF KHSYEDWLEN NGLSISPFHI RWQTAVFNRA 

        70         80         90        100        110        120 
FYSWGRRKAR MLYQWFNFGM VFGVIAMFSS FFLLGKTLMQ TLAQMMADSP SSYSSSSSSS 

       130        140        150        160        170        180 
SSSSSSSSSS SSSSSSLHNE QVLQVVVPGI NLPVNQLTYF FTAVLISGVV HEIGHGIAAI 

       190        200        210        220        230        240 
REQVRFNGFG IFLFIIYPGA FVDLFTTHLQ LISPVQQLRI FCAGIWHNFV LALLGILALV 

       250        260        270        280        290        300 
LLPVILLPFY YTGVGVLITE VAEDSPAIGP RGLFVGDLVT HLQDCPVTNV QDWNECLDTI 

       310        320        330        340        350        360 
AYEPQIGYCI SASTLQQLSF PVRAYKRLDG STECCNNHSL TDVCFSYRNN FNKRLHTCLP 

       370        380        390        400        410        420 
ARKAVEATQV CRTNKDCKKS SSSSFCIIPS LETHTRLIKV KHPPQIDMLY VGHPLHLHYT 

       430        440        450        460        470        480 
VSITSFIPRF NFLSIDLPVV VETFVKYLIS LSGALAIVNA VPCFALDGQW ILNSFLDATL 

       490        500        510 
TSVIGDNDVK DLIGFFILLG GSVLLAANVT LGLWMVTAR 

« Hide

References

« Hide 'large scale' references
[1]"Complementation cloning of S2P, a gene encoding a putative metalloprotease required for intramembrane cleavage of SREBPs."
Rawson R.B., Zelenski N.G., Nijhawan D., Ye J., Sakai J., Hasan M.T., Chang T.Y., Brown M.S., Goldstein J.L.
Mol. Cell 1:47-57(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], MUTAGENESIS OF HIS-171; GLU-172; HIS-175 AND ASP-467.
Tissue: Fibroblast.
[2]"The DNA sequence of the human X chromosome."
Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D., Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A., Lovell F.L., Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G., Jones M.C. expand/collapse author list , Hurles M.E., Andrews T.D., Scott C.E., Searle S., Ramser J., Whittaker A., Deadman R., Carter N.P., Hunt S.E., Chen R., Cree A., Gunaratne P., Havlak P., Hodgson A., Metzker M.L., Richards S., Scott G., Steffen D., Sodergren E., Wheeler D.A., Worley K.C., Ainscough R., Ambrose K.D., Ansari-Lari M.A., Aradhya S., Ashwell R.I., Babbage A.K., Bagguley C.L., Ballabio A., Banerjee R., Barker G.E., Barlow K.F., Barrett I.P., Bates K.N., Beare D.M., Beasley H., Beasley O., Beck A., Bethel G., Blechschmidt K., Brady N., Bray-Allen S., Bridgeman A.M., Brown A.J., Brown M.J., Bonnin D., Bruford E.A., Buhay C., Burch P., Burford D., Burgess J., Burrill W., Burton J., Bye J.M., Carder C., Carrel L., Chako J., Chapman J.C., Chavez D., Chen E., Chen G., Chen Y., Chen Z., Chinault C., Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S., Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S., Corby N., Connor R.E., David R., Davies J., Davis C., Davis J., Delgado O., Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S., Draper H., Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I., Eades T., Ellwood M., Emery-Cohen A., Errington H., Evans K.L., Faulkner L., Francis F., Frankland J., Fraser A.E., Galgoczy P., Gilbert J., Gill R., Gloeckner G., Gregory S.G., Gribble S., Griffiths C., Grocock R., Gu Y., Gwilliam R., Hamilton C., Hart E.A., Hawes A., Heath P.D., Heitmann K., Hennig S., Hernandez J., Hinzmann B., Ho S., Hoffs M., Howden P.J., Huckle E.J., Hume J., Hunt P.J., Hunt A.R., Isherwood J., Jacob L., Johnson D., Jones S., de Jong P.J., Joseph S.S., Keenan S., Kelly S., Kershaw J.K., Khan Z., Kioschis P., Klages S., Knights A.J., Kosiura A., Kovar-Smith C., Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., Liu W., Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D., Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H., McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T., Milne S., Miner G., Mistry S.L., Morgan M., Morris S., Mueller I., Mullikin J.C., Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N., Okwuonu G., Palmer S., Pandian R., Parker D., Parrish J., Pasternak S., Patel D., Pearce A.V., Pearson D.M., Pelan S.E., Perez L., Porter K.M., Ramsey Y., Reichwald K., Rhodes S., Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K., Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D., Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R., Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T., Teague B., Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S., Tromans A.C., d'Urso M., Verduzco D., Villasana D., Waldron L., Wall M., Wang Q., Warren J., Warry G.L., Wei X., West A., Whitehead S.L., Whiteley M.N., Wilkinson J.E., Willey D.L., Williams G., Williams L., Williamson A., Williamson H., Wilming L., Woodmansey R.L., Wray P.W., Yen J., Zhang J., Zhou J., Zoghbi H., Zorilla S., Buck D., Reinhardt R., Poustka A., Rosenthal A., Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F., Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A., Nelson D.L., Weinstock G., Sulston J.E., Durbin R.M., Hubbard T., Gibbs R.A., Beck S., Rogers J., Bentley D.R.
Nature 434:325-337(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]"Membrane topology of S2P, a protein required for intramembranous cleavage of sterol regulatory element-binding proteins."
Zelenski N.G., Rawson R.B., Brown M.S., Goldstein J.L.
J. Biol. Chem. 274:21973-21980(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: TOPOLOGY, GLYCOSYLATION AT ASN-337.
[4]"Asparagine-proline sequence within membrane-spanning segment of SREBP triggers intramembrane cleavage by site-2 protease."
Ye J., Dave U.P., Grishin N.V., Goldstein J.L., Brown M.S.
Proc. Natl. Acad. Sci. U.S.A. 97:5123-5128(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: CHARACTERIZATION.
[5]"IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response."
Oeffner F., Fischer G., Happle R., Konig A., Betz R.C., Bornholdt D., Neidel U., Boente Mdel C., Redler S., Romero-Gomez J., Salhi A., Vera-Casano A., Weirich C., Grzeschik K.H.
Am. J. Hum. Genet. 84:459-467(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION, VARIANTS IFAPS ILE-87; LEU-226; LEU-227; HIS-429 AND SER-475, CHARACTERIZATION OF VARIANTS IFAPS ILE-87; LEU-226; LEU-227; HIS-429 AND SER-475.
[6]"Keratosis follicularis spinulosa decalvans is caused by mutations in MBTPS2."
Aten E., Brasz L.C., Bornholdt D., Hooijkaas I.B., Porteous M.E., Sybert V.P., Vermeer M.H., Vossen R.H., van der Wielen M.J., Bakker E., Breuning M.H., Grzeschik K.H., Oosterwijk J.C., den Dunnen J.T.
Hum. Mutat. 31:1125-1133(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT KFSDX SER-508, CHARACTERIZATION OF VARIANT KFSDX SER-508.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AF019612 mRNA. Translation: AAC51937.1.
U73479 Genomic DNA. Translation: AAD08632.1.
U72788 Genomic DNA. Translation: AAD08631.1.
RefSeqNP_056968.1. NM_015884.3.
UniGeneHs.443490.

3D structure databases

ProteinModelPortalO43462.
SMRO43462. Positions 161-238, 254-288.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid119495. 1 interaction.
STRING9606.ENSP00000368798.

Protein family/group databases

MEROPSM50.001.

PTM databases

PhosphoSiteO43462.

Proteomic databases

PaxDbO43462.
PRIDEO43462.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000379484; ENSP00000368798; ENSG00000012174.
GeneID51360.
KEGGhsa:51360.
UCSCuc004dae.3. human.

Organism-specific databases

CTD51360.
GeneCardsGC0XP021857.
HGNCHGNC:15455. MBTPS2.
HPACAB009486.
HPA005494.
MIM300294. gene.
308205. phenotype.
308800. phenotype.
neXtProtNX_O43462.
Orphanet85284. BRESEK syndrome.
2273. Ichthyosis follicularis - alopecia - photophobia.
2340. Keratosis follicularis spinulosa decalvans.
659. Mutilating palmoplantar keratoderma with periorificial keratotic plaques.
PharmGKBPA30672.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0750.
HOGENOMHOG000231255.
HOVERGENHBG006397.
InParanoidO43462.
KOK07765.
OMAHLQYTVS.
OrthoDBEOG7WMCJB.
PhylomeDBO43462.
TreeFamTF314478.

Enzyme and pathway databases

BRENDA3.4.24.85. 2681.
ReactomeREACT_111217. Metabolism.
REACT_17015. Metabolism of proteins.

Gene expression databases

ArrayExpressO43462.
BgeeO43462.
CleanExHS_MBTPS2.
GenevestigatorO43462.

Family and domain databases

InterProIPR001193. MBTPS2.
IPR001478. PDZ.
IPR008915. Peptidase_M50.
[Graphical view]
PANTHERPTHR13325. PTHR13325. 1 hit.
PfamPF02163. Peptidase_M50. 1 hit.
[Graphical view]
PRINTSPR01000. SREBPS2PTASE.
SUPFAMSSF50156. SSF50156. 1 hit.
PROSITEPS00142. ZINC_PROTEASE. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSMBTPS2. human.
GenomeRNAi51360.
NextBio54814.
PROO43462.
SOURCESearch...

Entry information

Entry nameMBTP2_HUMAN
AccessionPrimary (citable) accession number: O43462
Secondary accession number(s): Q9UM70, Q9UMD3
Entry history
Integrated into UniProtKB/Swiss-Prot: July 15, 1999
Last sequence update: June 1, 1998
Last modified: April 16, 2014
This is version 124 of the entry and version 1 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 X

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