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Protein

Membrane-bound transcription factor site-2 protease

Gene

MBTPS2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -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

GO - Biological processi

Keywordsi

Molecular functionHydrolase, Metalloprotease, Protease
Biological processCholesterol metabolism, Lipid metabolism, Steroid metabolism, Sterol metabolism
LigandMetal-binding, Zinc

Enzyme and pathway databases

BRENDAi3.4.24.85 2681
ReactomeiR-HSA-1655829 Regulation of cholesterol biosynthesis by SREBP (SREBF)
R-HSA-381033 ATF6 (ATF6-alpha) activates chaperones
R-HSA-8874211 CREB3 factors activate genes
R-HSA-8963889 Assembly of active LPL and LIPC lipase complexes
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

EuPathDBiHostDB:ENSG00000012174.11
HGNCiHGNC:15455 MBTPS2
MIMi300294 gene
neXtProtiNX_O43462

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

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

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 dbSNP:rs122468177EnsemblClinVar.1
Natural variantiVAR_063055226W → L in IFAPS; does not affect subcellular localization; impairs activity. 1 PublicationCorresponds to variant dbSNP:rs122468180EnsemblClinVar.1
Natural variantiVAR_063056227H → L in IFAPS; does not affect subcellular localization; impairs activity. 1 PublicationCorresponds to variant dbSNP:rs122468176EnsemblClinVar.1
Natural variantiVAR_063057429R → H in IFAPS; does not affect subcellular localization; impairs activity. 1 PublicationCorresponds to variant dbSNP:rs122468178EnsemblClinVar.1
Natural variantiVAR_063058475F → S in IFAPS; does not affect subcellular localization; impairs activity. 1 PublicationCorresponds to variant dbSNP:rs122468179EnsemblClinVar.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 dbSNP:rs587777306EnsemblClinVar.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 dbSNP:rs587776867EnsemblClinVar.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 syndrome
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...) asparagine1 Publication1

Keywords - PTMi

Glycoprotein

Proteomic databases

EPDiO43462
MaxQBiO43462
PaxDbiO43462
PeptideAtlasiO43462
PRIDEiO43462
ProteomicsDBi48956

PTM databases

iPTMnetiO43462
PhosphoSitePlusiO43462

Expressioni

Tissue specificityi

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

Gene expression databases

BgeeiENSG00000012174 Expressed in 200 organ(s), highest expression level in endothelial cell
CleanExiHS_MBTPS2
ExpressionAtlasiO43462 baseline and differential
GenevisibleiO43462 HS

Organism-specific databases

HPAiCAB009486
HPA005494

Interactioni

Protein-protein interaction databases

BioGridi119495, 54 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
OMAiHYPYDAF
OrthoDBiEOG091G05YC
PhylomeDBiO43462
TreeFamiTF314478

Family and domain databases

InterProiView protein in InterPro
IPR001193 MBTPS2
IPR036034 PDZ_sf
IPR008915 Peptidase_M50
PANTHERiPTHR13325 PTHR13325, 1 hit
PfamiView protein in Pfam
PF02163 Peptidase_M50, 1 hit
PRINTSiPR01000 SREBPS2PTASE
SUPFAMiSSF50156 SSF50156, 1 hit
PROSITEiView protein in PROSITE
PS00142 ZINC_PROTEASE, 1 hit

Sequence (1+)i

Sequence statusi: Complete.

This entry has 1 described isoform and 1 potential isoform that is computationally mapped.Show allAlign All

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

Computationally mapped potential isoform sequencesi

There is 1 potential isoform mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
B9ZVQ3B9ZVQ3_HUMAN
Membrane-bound transcription factor...
MBTPS2
330Annotation score:

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_06305487M → I in IFAPS; does not affect subcellular localization; impairs activity. 1 PublicationCorresponds to variant dbSNP:rs122468177EnsemblClinVar.1
Natural variantiVAR_063055226W → L in IFAPS; does not affect subcellular localization; impairs activity. 1 PublicationCorresponds to variant dbSNP:rs122468180EnsemblClinVar.1
Natural variantiVAR_063056227H → L in IFAPS; does not affect subcellular localization; impairs activity. 1 PublicationCorresponds to variant dbSNP:rs122468176EnsemblClinVar.1
Natural variantiVAR_063057429R → H in IFAPS; does not affect subcellular localization; impairs activity. 1 PublicationCorresponds to variant dbSNP:rs122468178EnsemblClinVar.1
Natural variantiVAR_071323464F → S in OLMSX. 1 PublicationCorresponds to variant dbSNP:rs587777306EnsemblClinVar.1
Natural variantiVAR_063058475F → S in IFAPS; does not affect subcellular localization; impairs activity. 1 PublicationCorresponds to variant dbSNP:rs122468179EnsemblClinVar.1
Natural variantiVAR_064409508N → S in KFSDX; sterol responsiveness is reduced by half. 1 PublicationCorresponds to variant dbSNP:rs587776867EnsemblClinVar.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

Similar proteinsi

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, 54 interactors
STRINGi9606.ENSP00000368798

Protein family/group databases

MEROPSiM50.001

PTM databases

iPTMnetiO43462
PhosphoSitePlusiO43462

Polymorphism and mutation databases

BioMutaiMBTPS2

Proteomic databases

EPDiO43462
MaxQBiO43462
PaxDbiO43462
PeptideAtlasiO43462
PRIDEiO43462
ProteomicsDBi48956

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

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

Organism-specific databases

CTDi51360
DisGeNETi51360
EuPathDBiHostDB:ENSG00000012174.11
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 syndrome
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
OMAiHYPYDAF
OrthoDBiEOG091G05YC
PhylomeDBiO43462
TreeFamiTF314478

Enzyme and pathway databases

BRENDAi3.4.24.85 2681
ReactomeiR-HSA-1655829 Regulation of cholesterol biosynthesis by SREBP (SREBF)
R-HSA-381033 ATF6 (ATF6-alpha) activates chaperones
R-HSA-8874211 CREB3 factors activate genes
R-HSA-8963889 Assembly of active LPL and LIPC lipase complexes
SIGNORiO43462

Miscellaneous databases

ChiTaRSiMBTPS2 human
GenomeRNAii51360
PROiPR:O43462
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000012174 Expressed in 200 organ(s), highest expression level in endothelial cell
CleanExiHS_MBTPS2
ExpressionAtlasiO43462 baseline and differential
GenevisibleiO43462 HS

Family and domain databases

InterProiView protein in InterPro
IPR001193 MBTPS2
IPR036034 PDZ_sf
IPR008915 Peptidase_M50
PANTHERiPTHR13325 PTHR13325, 1 hit
PfamiView protein in Pfam
PF02163 Peptidase_M50, 1 hit
PRINTSiPR01000 SREBPS2PTASE
SUPFAMiSSF50156 SSF50156, 1 hit
PROSITEiView protein in PROSITE
PS00142 ZINC_PROTEASE, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiMBTP2_HUMAN
AccessioniPrimary (citable) accession number: O43462
Secondary accession number(s): Q9UM70, Q9UMD3
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 15, 1999
Last sequence update: June 1, 1998
Last modified: November 7, 2018
This is version 165 of the entry and version 1 of the sequence. See 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. SIMILARITY comments
    Index of protein domains and families
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Peptidase families
    Classification of peptidase families and list of entries
  4. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  5. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  6. Human chromosome X
    Human chromosome X: entries, gene names and cross-references to MIM
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Main funding by: National Institutes of Health

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