Reviewed, UniProtKB/Swiss-Prot O43462 (MBTP2_HUMAN)

Names and origin

Protein names

Recommended name:
    Membrane-bound transcription factor site-2 protease
      Short name=Site-2 protease
    EC=3.4.24.85
Alternative name(s):
    S2P endopeptidase
    Sterol regulatory element-binding proteins intramembrane protease

Gene names

Name:	MBTPS2
Synonyms:	S2P

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	519 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
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 proteinProbable.
Tissue specificity	Expressed in heart, brain, placenta, lung, liver, muscle, kidney and pancreas.
Sequence similarities	Belongs to the peptidase M50A family.

Ontologies

Keywords
Biological process	Cholesterol metabolism Lipid metabolism Steroid metabolism
Cellular component	Membrane
Domain	Transmembrane
Ligand	Metal-binding Zinc
Molecular function	Hydrolase Metalloprotease Protease
PTM	Glycoprotein
Gene Ontology (GO)
Biological process	cholesterol metabolic process Ref.1 Traceable author statement. Source: ProtInc proteolysis Inferred from electronic annotation. Source: InterPro
Cellular component	integral to membrane Ref.1 Traceable author statement. Source: ProtInc
Molecular function	metalloendopeptidase activity Ref.1 Traceable author statement. Source: ProtInc zinc ion binding Inferred from electronic annotation. Source: InterPro
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	Potential
	Topological domain	25 – 74	50	Lumenal Probable
	Transmembrane	75 – 95	21	Potential
	Transmembrane	96 – 107	12	Potential
	Topological domain	108 – 144	37	Lumenal Probable
	Transmembrane	145 – 169	25	Potential
	Transmembrane	174 – 186	13	Potential
	Transmembrane	187 – 209	23	Potential
	Transmembrane	229 – 251	23	Potential
	Topological domain	252 – 446	195	Lumenal Probable
	Transmembrane	447 – 464	18	Potential
	Transmembrane	465 – 476	12	Potential
	Topological domain	477 – 492	16	Lumenal Potential
	Transmembrane	493 – 513	21	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
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)
	O43462-1 [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: 9659902] [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: 15772651] [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: 10419520] [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: 10805775] [Abstract] Cited for: CHARACTERIZATION.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBLGenBankDDBJ	AF019612 mRNA. Translation: AAC51937.1. U73479 Genomic DNA. Translation: AAD08632.1. U72788 Genomic DNA. Translation: AAD08631.1.
RefSeq	NP_056968.1.
UniGene	Hs.585245
3D structure databases
ModBase	Search...
Protein family/group databases
MEROPS	M50.001.
Proteomic databases
PRIDE	O43462.
Genome annotation databases
Ensembl	ENSG00000012174. Homo sapiens. [Contig view]
GeneID	51360.
KEGG	hsa:51360.
NMPDR	fig|9606.3.peg.32542.
Organism-specific databases
GeneCards	GC0XP021767.
H-InvDB	HIX0016696.
HGNC	HGNC:15455. MBTPS2.
HPA	CAB009486. HPA005494.
MIM	300294. gene.
PharmGKB	PA30672.
GenAtlas	Search...
Phylogenomic databases
HOGENOM	O43462.
HOVERGEN	O43462.
Gene expression databases
ArrayExpress	O43462.
CleanEx	HS_MBTPS2.
GermOnline	ENSG00000012174. Homo sapiens.
Family and domain databases
InterPro	IPR001193. Pept_M50_SREBP. IPR006025. Pept_M_Zn_BS. IPR008915. Peptidase_M50. [Graphical view]
Pfam	PF02163. Peptidase_M50. 1 hit. [Graphical view]
PRINTS	PR01000. SREBPS2PTASE.
PROSITE	PS00142. ZINC_PROTEASE. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
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:	December 16, 2008
This is version 73 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)