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Protein

Membrane-bound transcription factor site-2 protease

Gene

MBTPS2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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 activityi

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.

Cofactori

Zn2+Note: Binds 1 zinc ion per subunit.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Metal bindingi171Zinc; catalytic1
Active sitei1721
Metal bindingi175Zinc; catalytic1

GO - Molecular functioni

  • metal ion binding Source: UniProtKB-KW
  • metalloendopeptidase activity Source: ProtInc
  • metallopeptidase activity Source: Reactome

GO - Biological processi

  • ATF6-mediated unfolded protein response Source: ParkinsonsUK-UCL
  • cholesterol metabolic process Source: ProtInc
  • membrane protein intracellular domain proteolysis Source: ParkinsonsUK-UCL
  • positive regulation of sequence-specific DNA binding transcription factor activity Source: ParkinsonsUK-UCL
  • positive regulation of transcription from RNA polymerase II promoter in response to endoplasmic reticulum stress Source: ParkinsonsUK-UCL
  • response to endoplasmic reticulum stress Source: ParkinsonsUK-UCL
Complete GO annotation...

Keywords - Molecular functioni

Hydrolase, Metalloprotease, Protease

Keywords - Biological processi

Cholesterol metabolism, Lipid metabolism, Steroid metabolism, Sterol metabolism

Keywords - Ligandi

Metal-binding, Zinc

Enzyme and pathway databases

BioCyciZFISH:ENSG00000012174-MONOMER.
ZFISH:G66-33948-MONOMER.
BRENDAi3.4.24.85. 2681.
ReactomeiR-HSA-1655829. Regulation of cholesterol biosynthesis by SREBP (SREBF).
R-HSA-174800. Chylomicron-mediated lipid transport.
R-HSA-381033. ATF6 (ATF6-alpha) activates chaperones.
SIGNORiO43462.

Protein family/group databases

MEROPSiM50.001.

Names & Taxonomyi

Protein namesi
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 namesi
Name:MBTPS2
Synonyms:S2P
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome X

Organism-specific databases

HGNCiHGNC:15455. MBTPS2.

Subcellular locationi

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 3Cytoplasmic1 Publication3
Transmembranei4 – 24HelicalSequence analysisAdd BLAST21
Topological domaini25 – 74Lumenal1 PublicationAdd BLAST50
Transmembranei75 – 95HelicalSequence analysisAdd BLAST21
Transmembranei96 – 107HelicalSequence analysisAdd BLAST12
Topological domaini108 – 144Lumenal1 PublicationAdd BLAST37
Transmembranei145 – 169HelicalSequence analysisAdd BLAST25
Transmembranei174 – 186HelicalSequence analysisAdd BLAST13
Transmembranei187 – 209HelicalSequence analysisAdd BLAST23
Transmembranei229 – 251HelicalSequence analysisAdd BLAST23
Topological domaini252 – 446Lumenal1 PublicationAdd BLAST195
Transmembranei447 – 464HelicalSequence analysisAdd BLAST18
Transmembranei465 – 476HelicalSequence analysisAdd BLAST12
Topological domaini477 – 492LumenalSequence analysisAdd BLAST16
Transmembranei493 – 513HelicalSequence analysisAdd BLAST21
Topological domaini514 – 519CytoplasmicSequence analysis6

GO - Cellular componenti

  • cytoplasm Source: UniProtKB
  • Golgi membrane Source: Reactome
  • integral component of membrane Source: ProtInc
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Membrane

Pathology & Biotechi

Involvement in diseasei

IFAP syndrome with or without BRESHECK syndrome (IFAPS)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA 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.
See also OMIM:308205
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_06305487M → I in IFAPS; does not affect subcellular localization; impairs activity. 1 PublicationCorresponds to variant rs122468177dbSNPEnsembl.1
Natural variantiVAR_063055226W → L in IFAPS; does not affect subcellular localization; impairs activity. 1 PublicationCorresponds to variant rs122468180dbSNPEnsembl.1
Natural variantiVAR_063056227H → L in IFAPS; does not affect subcellular localization; impairs activity. 1 PublicationCorresponds to variant rs122468176dbSNPEnsembl.1
Natural variantiVAR_063057429R → H in IFAPS; does not affect subcellular localization; impairs activity. 1 PublicationCorresponds to variant rs122468178dbSNPEnsembl.1
Natural variantiVAR_063058475F → S in IFAPS; does not affect subcellular localization; impairs activity. 1 PublicationCorresponds to variant rs122468179dbSNPEnsembl.1
Olmsted syndrome, X-linked (OLMSX)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA rare congenital disorder characterized by bilateral mutilating palmoplantar keratoderma and periorificial keratotic plaques with severe itching at all lesions. Diffuse alopecia, constriction of digits, and onychodystrophy have also been reported. Infections and squamous cell carcinomas can arise on the keratotic areas. The digital constriction may progress to autoamputation of fingers and toes.
See also OMIM:300918
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_071323464F → S in OLMSX. 1 PublicationCorresponds to variant rs587777306dbSNPEnsembl.1
Keratosis follicularis spinulosa decalvans X-linked (KFSDX)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA 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.
See also OMIM:308800
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_064409508N → S in KFSDX; sterol responsiveness is reduced by half. 1 PublicationCorresponds to variant rs587776867dbSNPEnsembl.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi171H → F: Loss of activity. 1 Publication1
Mutagenesisi172E → A or Q: Loss of activity. 1 Publication1
Mutagenesisi172E → D: Partial loss of activity. 1 Publication1
Mutagenesisi175H → F: Loss of activity. 1 Publication1
Mutagenesisi467D → N: Loss of activity. 1 Publication1

Keywords - Diseasei

Disease mutation, Ichthyosis, Palmoplantar keratoderma

Organism-specific databases

DisGeNETi51360.
MalaCardsiMBTPS2.
MIMi300918. phenotype.
308205. phenotype.
308800. phenotype.
OpenTargetsiENSG00000012174.
Orphaneti85284. BRESEK syndrome.
2273. Ichthyosis follicularis - alopecia - photophobia.
2340. Keratosis follicularis spinulosa decalvans.
659. Mutilating palmoplantar keratoderma with periorificial keratotic plaques.
PharmGKBiPA30672.

Polymorphism and mutation databases

BioMutaiMBTPS2.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000884821 – 519Membrane-bound transcription factor site-2 proteaseAdd BLAST519

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Glycosylationi337N-linked (GlcNAc...)1 Publication1

Keywords - PTMi

Glycoprotein

Proteomic databases

MaxQBiO43462.
PaxDbiO43462.
PeptideAtlasiO43462.
PRIDEiO43462.

PTM databases

iPTMnetiO43462.
PhosphoSitePlusiO43462.

Expressioni

Tissue specificityi

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

Gene expression databases

BgeeiENSG00000012174.
CleanExiHS_MBTPS2.
ExpressionAtlasiO43462. baseline and differential.
GenevisibleiO43462. HS.

Organism-specific databases

HPAiCAB009486.
HPA005494.

Interactioni

Protein-protein interaction databases

BioGridi119495. 4 interactors.
STRINGi9606.ENSP00000368798.

Structurei

3D structure databases

ProteinModelPortaliO43462.
SMRiO43462.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi109 – 136Poly-SerAdd BLAST28
Compositional biasi285 – 386Cys-richAdd BLAST102
Compositional biasi380 – 384Poly-Ser5

Sequence similaritiesi

Belongs to the peptidase M50A family.Curated

Keywords - Domaini

Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG2921. Eukaryota.
COG0750. LUCA.
GeneTreeiENSGT00510000048066.
HOGENOMiHOG000231255.
HOVERGENiHBG006397.
InParanoidiO43462.
KOiK07765.
OMAiTELSHDH.
OrthoDBiEOG091G05YC.
PhylomeDBiO43462.
TreeFamiTF314478.

Family and domain databases

Gene3Di2.30.42.10. 1 hit.
InterProiIPR001193. MBTPS2.
IPR001478. PDZ.
IPR008915. Peptidase_M50.
[Graphical view]
PANTHERiPTHR13325. PTHR13325. 1 hit.
PfamiPF02163. Peptidase_M50. 1 hit.
[Graphical view]
PRINTSiPR01000. SREBPS2PTASE.
SUPFAMiSSF50156. SSF50156. 1 hit.
PROSITEiPS00142. ZINC_PROTEASE. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

O43462-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MIPVSLVVVV VGGWTVVYLT DLVLKSSVYF KHSYEDWLEN NGLSISPFHI
60 70 80 90 100
RWQTAVFNRA FYSWGRRKAR MLYQWFNFGM VFGVIAMFSS FFLLGKTLMQ
110 120 130 140 150
TLAQMMADSP SSYSSSSSSS SSSSSSSSSS SSSSSSLHNE QVLQVVVPGI
160 170 180 190 200
NLPVNQLTYF FTAVLISGVV HEIGHGIAAI REQVRFNGFG IFLFIIYPGA
210 220 230 240 250
FVDLFTTHLQ LISPVQQLRI FCAGIWHNFV LALLGILALV LLPVILLPFY
260 270 280 290 300
YTGVGVLITE VAEDSPAIGP RGLFVGDLVT HLQDCPVTNV QDWNECLDTI
310 320 330 340 350
AYEPQIGYCI SASTLQQLSF PVRAYKRLDG STECCNNHSL TDVCFSYRNN
360 370 380 390 400
FNKRLHTCLP ARKAVEATQV CRTNKDCKKS SSSSFCIIPS LETHTRLIKV
410 420 430 440 450
KHPPQIDMLY VGHPLHLHYT VSITSFIPRF NFLSIDLPVV VETFVKYLIS
460 470 480 490 500
LSGALAIVNA VPCFALDGQW ILNSFLDATL TSVIGDNDVK DLIGFFILLG
510
GSVLLAANVT LGLWMVTAR
Length:519
Mass (Da):57,444
Last modified:June 1, 1998 - v1
Checksum:i247D69E0FD7747BD
GO

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_06305487M → I in IFAPS; does not affect subcellular localization; impairs activity. 1 PublicationCorresponds to variant rs122468177dbSNPEnsembl.1
Natural variantiVAR_063055226W → L in IFAPS; does not affect subcellular localization; impairs activity. 1 PublicationCorresponds to variant rs122468180dbSNPEnsembl.1
Natural variantiVAR_063056227H → L in IFAPS; does not affect subcellular localization; impairs activity. 1 PublicationCorresponds to variant rs122468176dbSNPEnsembl.1
Natural variantiVAR_063057429R → H in IFAPS; does not affect subcellular localization; impairs activity. 1 PublicationCorresponds to variant rs122468178dbSNPEnsembl.1
Natural variantiVAR_071323464F → S in OLMSX. 1 PublicationCorresponds to variant rs587777306dbSNPEnsembl.1
Natural variantiVAR_063058475F → S in IFAPS; does not affect subcellular localization; impairs activity. 1 PublicationCorresponds to variant rs122468179dbSNPEnsembl.1
Natural variantiVAR_064409508N → S in KFSDX; sterol responsiveness is reduced by half. 1 PublicationCorresponds to variant rs587776867dbSNPEnsembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF019612 mRNA. Translation: AAC51937.1.
U73479 Genomic DNA. Translation: AAD08632.1.
U72788 Genomic DNA. Translation: AAD08631.1.
CCDSiCCDS14201.1.
RefSeqiNP_056968.1. NM_015884.3.
UniGeneiHs.443490.

Genome annotation databases

EnsembliENST00000379484; ENSP00000368798; ENSG00000012174.
GeneIDi51360.
KEGGihsa:51360.
UCSCiuc004dae.4. human.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF019612 mRNA. Translation: AAC51937.1.
U73479 Genomic DNA. Translation: AAD08632.1.
U72788 Genomic DNA. Translation: AAD08631.1.
CCDSiCCDS14201.1.
RefSeqiNP_056968.1. NM_015884.3.
UniGeneiHs.443490.

3D structure databases

ProteinModelPortaliO43462.
SMRiO43462.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi119495. 4 interactors.
STRINGi9606.ENSP00000368798.

Protein family/group databases

MEROPSiM50.001.

PTM databases

iPTMnetiO43462.
PhosphoSitePlusiO43462.

Polymorphism and mutation databases

BioMutaiMBTPS2.

Proteomic databases

MaxQBiO43462.
PaxDbiO43462.
PeptideAtlasiO43462.
PRIDEiO43462.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000379484; ENSP00000368798; ENSG00000012174.
GeneIDi51360.
KEGGihsa:51360.
UCSCiuc004dae.4. human.

Organism-specific databases

CTDi51360.
DisGeNETi51360.
GeneCardsiMBTPS2.
HGNCiHGNC:15455. MBTPS2.
HPAiCAB009486.
HPA005494.
MalaCardsiMBTPS2.
MIMi300294. gene.
300918. phenotype.
308205. phenotype.
308800. phenotype.
neXtProtiNX_O43462.
OpenTargetsiENSG00000012174.
Orphaneti85284. BRESEK syndrome.
2273. Ichthyosis follicularis - alopecia - photophobia.
2340. Keratosis follicularis spinulosa decalvans.
659. Mutilating palmoplantar keratoderma with periorificial keratotic plaques.
PharmGKBiPA30672.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG2921. Eukaryota.
COG0750. LUCA.
GeneTreeiENSGT00510000048066.
HOGENOMiHOG000231255.
HOVERGENiHBG006397.
InParanoidiO43462.
KOiK07765.
OMAiTELSHDH.
OrthoDBiEOG091G05YC.
PhylomeDBiO43462.
TreeFamiTF314478.

Enzyme and pathway databases

BioCyciZFISH:ENSG00000012174-MONOMER.
ZFISH:G66-33948-MONOMER.
BRENDAi3.4.24.85. 2681.
ReactomeiR-HSA-1655829. Regulation of cholesterol biosynthesis by SREBP (SREBF).
R-HSA-174800. Chylomicron-mediated lipid transport.
R-HSA-381033. ATF6 (ATF6-alpha) activates chaperones.
SIGNORiO43462.

Miscellaneous databases

ChiTaRSiMBTPS2. human.
GenomeRNAii51360.
PROiO43462.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000012174.
CleanExiHS_MBTPS2.
ExpressionAtlasiO43462. baseline and differential.
GenevisibleiO43462. HS.

Family and domain databases

Gene3Di2.30.42.10. 1 hit.
InterProiIPR001193. MBTPS2.
IPR001478. PDZ.
IPR008915. Peptidase_M50.
[Graphical view]
PANTHERiPTHR13325. PTHR13325. 1 hit.
PfamiPF02163. Peptidase_M50. 1 hit.
[Graphical view]
PRINTSiPR01000. SREBPS2PTASE.
SUPFAMiSSF50156. SSF50156. 1 hit.
PROSITEiPS00142. ZINC_PROTEASE. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiMBTP2_HUMAN
AccessioniPrimary (citable) accession number: O43462
Secondary accession number(s): Q9UM70, Q9UMD3
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 15, 1999
Last sequence update: June 1, 1998
Last modified: November 30, 2016
This is version 150 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (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.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome X
    Human chromosome X: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. Peptidase families
    Classification of peptidase families and list of entries
  6. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.