O43462 (MBTP2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	519 AA.
Sequence status	Complete.
Protein existence	Evidence 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.

Ontologies

Keywords
Biological process	Cholesterol metabolism Lipid metabolism Steroid metabolism Sterol metabolism
Cellular component	Cytoplasm Membrane
Disease	Disease mutation Ichthyosis
Domain	Transmembrane Transmembrane helix
Ligand	Metal-binding Zinc
Molecular function	Hydrolase Metalloprotease Protease
PTM	Glycoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	activation of signaling protein activity involved in unfolded protein response Traceable author statement. Source: Reactome cholesterol metabolic process Traceable author statement Ref.1. Source: ProtInc proteolysis Inferred from electronic annotation. Source: UniProtKB-KW
Cellular_component	Golgi membrane Traceable author statement. Source: Reactome integral to membrane Traceable author statement Ref.1. Source: ProtInc
Molecular_function	metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW metalloendopeptidase activity Traceable author statement Ref.1. Source: ProtInc
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 519	519	Membrane-bound transcription factor site-2 protease		PRO_0000088482
Regions
	Topological domain	1 – 3	3	Cytoplasmic Ref.3
	Transmembrane	4 – 24	21	Helical; Potential
	Topological domain	25 – 74	50	Lumenal Probable
	Transmembrane	75 – 95	21	Helical; Potential
	Transmembrane	96 – 107	12	Helical; Potential
	Topological domain	108 – 144	37	Lumenal Probable
	Transmembrane	145 – 169	25	Helical; Potential
	Transmembrane	174 – 186	13	Helical; Potential
	Transmembrane	187 – 209	23	Helical; Potential
	Transmembrane	229 – 251	23	Helical; Potential
	Topological domain	252 – 446	195	Lumenal Probable
	Transmembrane	447 – 464	18	Helical; Potential
	Transmembrane	465 – 476	12	Helical; Potential
	Topological domain	477 – 492	16	Lumenal Potential
	Transmembrane	493 – 513	21	Helical; Potential
	Topological domain	514 – 519	6	Cytoplasmic Potential
	Compositional bias	109 – 136	28	Poly-Ser
	Compositional bias	285 – 386	102	Cys-rich
	Compositional bias	380 – 384	5	Poly-Ser
Sites
	Active site	172	1
	Metal binding	171	1	Zinc; catalytic
	Metal binding	175	1	Zinc; catalytic
Amino acid modifications
	Glycosylation	337	1	N-linked (GlcNAc...) Ref.3
Natural variations
	Natural variant	87	1	M → I in IFAPS; does not affect subcellular localization; impairs activity. Ref.5		VAR_063054
	Natural variant	226	1	W → L in IFAPS; does not affect subcellular localization; impairs activity. Ref.5		VAR_063055
	Natural variant	227	1	H → L in IFAPS; does not affect subcellular localization; impairs activity. Ref.5		VAR_063056
	Natural variant	429	1	R → H in IFAPS; does not affect subcellular localization; impairs activity. Ref.5		VAR_063057
	Natural variant	475	1	F → S in IFAPS; does not affect subcellular localization; impairs activity. Ref.5		VAR_063058
	Natural variant	508	1	N → S in KFSDX; sterol responsiveness is reduced by half. Ref.6		VAR_064409
Experimental info
	Mutagenesis	171	1	H → F: Loss of activity. Ref.1
	Mutagenesis	172	1	E → A or Q: Loss of activity. Ref.1
	Mutagenesis	172	1	E → D: Partial loss of activity. Ref.1
	Mutagenesis	175	1	H → F: Loss of activity. Ref.1
	Mutagenesis	467	1	D → N: Loss of activity. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	O43462 [UniParc]. Last modified June 1, 1998. Version 1. Checksum: 247D69E0FD7747BD	FASTA	519	57,444
	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

References

	« Hide 'large scale' referencesShow '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. , 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.
IPI	IPI00328263.
RefSeq	NP_056968.1. NM_015884.3.
UniGene	Hs.443490.
3D structure databases
ProteinModelPortal	O43462.
ModBase	Search...
Protein-protein interaction databases
STRING	9606.ENSP00000368798.
Protein family/group databases
MEROPS	M50.001.
PTM databases
PhosphoSite	O43462.
Proteomic databases
PaxDb	O43462.
PRIDE	O43462.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000379484; ENSP00000368798; ENSG00000012174.
GeneID	51360.
KEGG	hsa:51360.
UCSC	uc004dae.3. human.
Organism-specific databases
CTD	51360.
GeneCards	GC0XP021857.
HGNC	HGNC:15455. MBTPS2.
HPA	CAB009486. HPA005494.
MIM	300294. gene. 308205. phenotype. 308800. phenotype.
neXtProt	NX_O43462.
Orphanet	85284. BRESEK syndrome. 2273. Ichthyosis follicularis - alopecia - photophobia. 2340. Keratosis follicularis spinulosa decalvans.
PharmGKB	PA30672.
GenAtlas	Search...
Phylogenomic databases
eggNOG	COG0750.
HOGENOM	HOG000231255.
HOVERGEN	HBG006397.
InParanoid	O43462.
KO	K07765.
OMA	SLENQTR.
OrthoDB	EOG4WQ12G.
PhylomeDB	O43462.
Enzyme and pathway databases
BRENDA	3.4.24.85. 2681.
Reactome	REACT_111217. Metabolism. REACT_116125. Disease.
Gene expression databases
ArrayExpress	O43462.
Bgee	O43462.
CleanEx	HS_MBTPS2.
Genevestigator	O43462.
GermOnline	ENSG00000012174. Homo sapiens.
Family and domain databases
InterPro	IPR008915. Peptidase_M50. IPR001193. SREBP_intramem_Prtase. [Graphical view]
PANTHER	PTHR13325. PTHR13325. 1 hit.
Pfam	PF02163. Peptidase_M50. 1 hit. [Graphical view]
PRINTS	PR01000. SREBPS2PTASE.
PROSITE	PS00142. ZINC_PROTEASE. 1 hit. [Graphical view]
ProtoNet	Search...
Other
ChiTaRS	MBTPS2. human.
GenomeRNAi	51360.
NextBio	54814.
SOURCE	Search...

Entry information

Entry name

MBTP2_HUMAN

Accession

Primary (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:	May 1, 2013
This is version 115 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.