O43462 · MBTP2_HUMAN
- ProteinMembrane-bound transcription factor site-2 protease
- GeneMBTPS2
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids519 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Zinc metalloprotease that mediates intramembrane proteolysis of proteins such as ATF6, ATF6B, SREBF1/SREBP1 and SREBF2/SREBP2 (PubMed:10805775, PubMed:11163209).
Catalyzes the second step in the proteolytic activation of the sterol regulatory element-binding proteins (SREBPs) SREBF1/SREBP1 and SREBF2/SREBP2: cleaves SREBPs within the first transmembrane segment, thereby releasing the N-terminal segment with a portion of the transmembrane segment attached (PubMed:10805775, PubMed:27380894, PubMed:9659902).
Mature N-terminal SREBP fragments shuttle to the nucleus and activate gene transcription (PubMed:10805775, PubMed:27380894, PubMed:9659902).
Also mediates the second step in the proteolytic activation of the cyclic AMP-dependent transcription factor ATF-6 (ATF6 and ATF6B) (PubMed:11163209).
Involved in intramembrane proteolysis during bone formation (PubMed:27380894).
In astrocytes and osteoblasts, upon DNA damage and ER stress, mediates the second step of the regulated intramembrane proteolytic activation of the transcription factor CREB3L1, leading to the inhibition of cell-cycle progression (PubMed:16417584).
Catalyzes the second step in the proteolytic activation of the sterol regulatory element-binding proteins (SREBPs) SREBF1/SREBP1 and SREBF2/SREBP2: cleaves SREBPs within the first transmembrane segment, thereby releasing the N-terminal segment with a portion of the transmembrane segment attached (PubMed:10805775, PubMed:27380894, PubMed:9659902).
Mature N-terminal SREBP fragments shuttle to the nucleus and activate gene transcription (PubMed:10805775, PubMed:27380894, PubMed:9659902).
Also mediates the second step in the proteolytic activation of the cyclic AMP-dependent transcription factor ATF-6 (ATF6 and ATF6B) (PubMed:11163209).
Involved in intramembrane proteolysis during bone formation (PubMed:27380894).
In astrocytes and osteoblasts, upon DNA damage and ER stress, mediates the second step of the regulated intramembrane proteolytic activation of the transcription factor CREB3L1, leading to the inhibition of cell-cycle progression (PubMed:16417584).
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
Note: Binds 1 zinc ion per subunit.
Features
Showing features for binding site, active site.
GO annotations
Aspect | Term | |
---|---|---|
Cellular Component | cytoplasm | |
Cellular Component | Golgi membrane | |
Cellular Component | membrane | |
Molecular Function | metal ion binding | |
Molecular Function | metalloendopeptidase activity | |
Molecular Function | transcription regulator activator activity | |
Biological Process | ATF6-mediated unfolded protein response | |
Biological Process | bone maturation | |
Biological Process | cholesterol metabolic process | |
Biological Process | endoplasmic reticulum unfolded protein response | |
Biological Process | membrane protein intracellular domain proteolysis | |
Biological Process | mitotic G2 DNA damage checkpoint signaling | |
Biological Process | positive regulation of transcription by RNA polymerase II | |
Biological Process | protein maturation | |
Biological Process | regulation of cholesterol biosynthetic process | |
Biological Process | regulation of response to endoplasmic reticulum stress | |
Biological Process | response to endoplasmic reticulum stress |
Keywords
- Molecular function
- Biological process
- Ligand
Enzyme and pathway databases
Protein family/group databases
Names & Taxonomy
Protein names
- Recommended nameMembrane-bound transcription factor site-2 protease
- EC number
- Alternative names
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionO43462
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Membrane ; Multi-pass membrane protein
Golgi apparatus membrane ; Multi-pass membrane protein
Features
Showing features for topological domain, transmembrane.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Topological domain | 1-3 | Cytoplasmic | ||||
Sequence: MIP | ||||||
Transmembrane | 4-24 | Helical | ||||
Sequence: VSLVVVVVGGWTVVYLTDLVL | ||||||
Topological domain | 25-74 | Lumenal | ||||
Sequence: KSSVYFKHSYEDWLENNGLSISPFHIRWQTAVFNRAFYSWGRRKARMLYQ | ||||||
Transmembrane | 75-95 | Helical | ||||
Sequence: WFNFGMVFGVIAMFSSFFLLG | ||||||
Transmembrane | 96-107 | Helical | ||||
Sequence: KTLMQTLAQMMA | ||||||
Topological domain | 108-144 | Lumenal | ||||
Sequence: DSPSSYSSSSSSSSSSSSSSSSSSSSSSSLHNEQVLQ | ||||||
Transmembrane | 145-169 | Helical | ||||
Sequence: VVVPGINLPVNQLTYFFTAVLISGV | ||||||
Transmembrane | 174-186 | Helical | ||||
Sequence: GHGIAAIREQVRF | ||||||
Transmembrane | 187-209 | Helical | ||||
Sequence: NGFGIFLFIIYPGAFVDLFTTHL | ||||||
Transmembrane | 229-251 | Helical | ||||
Sequence: FVLALLGILALVLLPVILLPFYY | ||||||
Topological domain | 252-446 | Lumenal | ||||
Sequence: TGVGVLITEVAEDSPAIGPRGLFVGDLVTHLQDCPVTNVQDWNECLDTIAYEPQIGYCISASTLQQLSFPVRAYKRLDGSTECCNNHSLTDVCFSYRNNFNKRLHTCLPARKAVEATQVCRTNKDCKKSSSSSFCIIPSLETHTRLIKVKHPPQIDMLYVGHPLHLHYTVSITSFIPRFNFLSIDLPVVVETFVK | ||||||
Transmembrane | 447-464 | Helical | ||||
Sequence: YLISLSGALAIVNAVPCF | ||||||
Transmembrane | 465-476 | Helical | ||||
Sequence: ALDGQWILNSFL | ||||||
Topological domain | 477-492 | Lumenal | ||||
Sequence: DATLTSVIGDNDVKDL | ||||||
Transmembrane | 493-513 | Helical | ||||
Sequence: IGFFILLGGSVLLAANVTLGL | ||||||
Topological domain | 514-519 | Cytoplasmic | ||||
Sequence: WMVTAR |
Keywords
- Cellular component
Disease & Variants
Involvement in disease
IFAP syndrome 1, with or without Bresheck syndrome (IFAP1)
- Note
- DescriptionAn X-linked 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 alsoMIM:308205
Natural variants in IFAP1
Variant ID | Position(s) | Change | Description | |
---|---|---|---|---|
VAR_063054 | 87 | M>I | in IFAP1; does not affect subcellular localization; impairs activity; dbSNP:rs122468177 | |
VAR_063055 | 226 | W>L | in IFAP1; does not affect subcellular localization; impairs activity; dbSNP:rs122468180 | |
VAR_063056 | 227 | H>L | in IFAP1; does not affect subcellular localization; impairs activity; dbSNP:rs122468176 | |
VAR_063057 | 429 | R>H | in IFAP1; does not affect subcellular localization; impairs activity; dbSNP:rs122468178 | |
VAR_063058 | 475 | F>S | in IFAP1; does not affect subcellular localization; impairs activity; dbSNP:rs122468179 |
Olmsted syndrome, X-linked (OLMSX)
- Note
- 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 alsoMIM:300918
Natural variants in OLMSX
Variant ID | Position(s) | Change | Description | |
---|---|---|---|---|
VAR_071323 | 464 | F>S | in OLMSX; dbSNP:rs587777306 |
Keratosis follicularis spinulosa decalvans X-linked (KFSDX)
- Note
- 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 alsoMIM:308800
Natural variants in KFSDX
Variant ID | Position(s) | Change | Description | |
---|---|---|---|---|
VAR_064409 | 508 | N>S | in KFSDX; sterol responsiveness is reduced by half; dbSNP:rs587776867 |
Osteogenesis imperfecta 19 (OI19)
- Note
- DescriptionAn X-linked form of osteogenesis imperfecta, a disorder of bone formation characterized by low bone mass, bone fragility and susceptibility to fractures after minimal trauma. Disease severity ranges from very mild forms without fractures to intrauterine fractures and perinatal lethality. Extraskeletal manifestations, which affect a variable number of patients, are dentinogenesis imperfecta, hearing loss, and blue sclerae. OI19 is characterized by prenatal fractures, short stature, white sclerae, variable scoliosis and pectal deformity, striking tibial anterior angulation and generalized osteopenia.
- See alsoMIM:301014
Natural variants in OI19
Variant ID | Position(s) | Change | Description | |
---|---|---|---|---|
VAR_081103 | 459 | N>S | in OI19; decreased regulated intramembrane proteolysis resulting in reduced transcriptional activation of genes relevant to osteoblast differentiation and bone formation; dbSNP:rs1555986267 | |
VAR_081104 | 505 | L>F | in OI19; decreased regulated intramembrane proteolysis resulting in reduced transcriptional activation of genes relevant to osteoblast differentiation and bone formation; dbSNP:rs1555986287 |
Features
Showing features for natural variant, mutagenesis.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Natural variant | VAR_063054 | 87 | in IFAP1; does not affect subcellular localization; impairs activity; dbSNP:rs122468177 | |||
Sequence: M → I | ||||||
Mutagenesis | 171 | Loss of activity. | ||||
Sequence: H → F | ||||||
Mutagenesis | 172 | Loss of activity. | ||||
Sequence: E → A or Q | ||||||
Mutagenesis | 172 | Partial loss of activity. | ||||
Sequence: E → D | ||||||
Mutagenesis | 175 | Loss of activity. | ||||
Sequence: H → F | ||||||
Natural variant | VAR_063055 | 226 | in IFAP1; does not affect subcellular localization; impairs activity; dbSNP:rs122468180 | |||
Sequence: W → L | ||||||
Natural variant | VAR_063056 | 227 | in IFAP1; does not affect subcellular localization; impairs activity; dbSNP:rs122468176 | |||
Sequence: H → L | ||||||
Natural variant | VAR_063057 | 429 | in IFAP1; does not affect subcellular localization; impairs activity; dbSNP:rs122468178 | |||
Sequence: R → H | ||||||
Natural variant | VAR_081103 | 459 | in OI19; decreased regulated intramembrane proteolysis resulting in reduced transcriptional activation of genes relevant to osteoblast differentiation and bone formation; dbSNP:rs1555986267 | |||
Sequence: N → S | ||||||
Natural variant | VAR_071323 | 464 | in OLMSX; dbSNP:rs587777306 | |||
Sequence: F → S | ||||||
Mutagenesis | 467 | Loss of activity. | ||||
Sequence: D → N | ||||||
Natural variant | VAR_063058 | 475 | in IFAP1; does not affect subcellular localization; impairs activity; dbSNP:rs122468179 | |||
Sequence: F → S | ||||||
Natural variant | VAR_081104 | 505 | in OI19; decreased regulated intramembrane proteolysis resulting in reduced transcriptional activation of genes relevant to osteoblast differentiation and bone formation; dbSNP:rs1555986287 | |||
Sequence: L → F | ||||||
Natural variant | VAR_064409 | 508 | in KFSDX; sterol responsiveness is reduced by half; dbSNP:rs587776867 | |||
Sequence: N → S |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 329 variants from UniProt as well as other sources including ClinVar and dbSNP.
Keywords
- Disease
Organism-specific databases
Miscellaneous
Genetic variation databases
PTM/Processing
Features
Showing features for chain, glycosylation.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000088482 | 1-519 | Membrane-bound transcription factor site-2 protease | |||
Sequence: MIPVSLVVVVVGGWTVVYLTDLVLKSSVYFKHSYEDWLENNGLSISPFHIRWQTAVFNRAFYSWGRRKARMLYQWFNFGMVFGVIAMFSSFFLLGKTLMQTLAQMMADSPSSYSSSSSSSSSSSSSSSSSSSSSSSLHNEQVLQVVVPGINLPVNQLTYFFTAVLISGVVHEIGHGIAAIREQVRFNGFGIFLFIIYPGAFVDLFTTHLQLISPVQQLRIFCAGIWHNFVLALLGILALVLLPVILLPFYYTGVGVLITEVAEDSPAIGPRGLFVGDLVTHLQDCPVTNVQDWNECLDTIAYEPQIGYCISASTLQQLSFPVRAYKRLDGSTECCNNHSLTDVCFSYRNNFNKRLHTCLPARKAVEATQVCRTNKDCKKSSSSSFCIIPSLETHTRLIKVKHPPQIDMLYVGHPLHLHYTVSITSFIPRFNFLSIDLPVVVETFVKYLISLSGALAIVNAVPCFALDGQWILNSFLDATLTSVIGDNDVKDLIGFFILLGGSVLLAANVTLGLWMVTAR | ||||||
Glycosylation | 337 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N |
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Tissue specificity
Expressed in heart, brain, placenta, lung, liver, muscle, kidney and pancreas.
Gene expression databases
Organism-specific databases
Structure
Family & Domains
Features
Showing features for region.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 115-135 | Disordered | ||||
Sequence: SSSSSSSSSSSSSSSSSSSSS |
Sequence similarities
Belongs to the peptidase M50A family.
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Length519
- Mass (Da)57,444
- Last updated1998-06-01 v1
- Checksum247D69E0FD7747BD
Computationally mapped potential isoform sequences
There is 1 potential isoform mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
B9ZVQ3 | B9ZVQ3_HUMAN | MBTPS2 | 330 |
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AF019612 EMBL· GenBank· DDBJ | AAC51937.1 EMBL· GenBank· DDBJ | mRNA | ||
U73479 EMBL· GenBank· DDBJ | AAD08632.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
U72788 EMBL· GenBank· DDBJ | AAD08631.1 EMBL· GenBank· DDBJ | Genomic DNA |