Q9UKV5 · AMFR_HUMAN
- ProteinE3 ubiquitin-protein ligase AMFR
- GeneAMFR
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids643 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
E3 ubiquitin-protein ligase that mediates the polyubiquitination of lysine and cysteine residues on target proteins, such as CD3D, CYP3A4, CFTR, INSIG1, SOAT2/ACAT2 and APOB for proteasomal degradation (PubMed:10456327, PubMed:11724934, PubMed:12670940, PubMed:19103148, PubMed:24424410, PubMed:28604676).
Component of a VCP/p97-AMFR/gp78 complex that participates in the final step of endoplasmic reticulum-associated degradation (ERAD) (PubMed:10456327, PubMed:11724934, PubMed:19103148, PubMed:24424410).
The VCP/p97-AMFR/gp78 complex is involved in the sterol-accelerated ERAD degradation of HMGCR through binding to the HMGCR-INSIG1 complex at the ER membrane (PubMed:16168377, PubMed:22143767).
In addition, interaction of AMFR with AUP1 facilitates interaction of AMFR with ubiquitin-conjugating enzyme UBE2G2 and ubiquitin ligase RNF139, leading to sterol-induced HMGCR ubiquitination (PubMed:23223569).
The ubiquitinated HMGCR is then released from the ER into the cytosol for subsequent destruction (PubMed:16168377, PubMed:22143767, PubMed:23223569).
In addition to ubiquitination on lysine residues, catalyzes ubiquitination on cysteine residues: together with INSIG1, mediates polyubiquitination of SOAT2/ACAT2 at 'Cys-277', leading to its degradation when the lipid levels are low (PubMed:28604676).
Catalyzes ubiquitination and subsequent degradation of INSIG1 when cells are depleted of sterols (PubMed:17043353).
Mediates polyubiquitination of INSIG2 at 'Cys-215' in some tissues, leading to its degradation (PubMed:31953408).
Also regulates ERAD through the ubiquitination of UBL4A a component of the BAG6/BAT3 complex (PubMed:21636303).
Also acts as a scaffold protein to assemble a complex that couples ubiquitination, retranslocation and deglycosylation (PubMed:21636303).
Mediates tumor invasion and metastasis as a receptor for the GPI/autocrine motility factor (PubMed:10456327).
In association with LMBR1L and UBAC2, negatively regulates the canonical Wnt signaling pathway in the lymphocytes by promoting the ubiquitin-mediated degradation of CTNNB1 and Wnt receptors FZD6 and LRP6 (PubMed:31073040).
Regulates NF-kappa-B and MAPK signaling pathways by mediating 'Lys-27'-linked polyubiquitination of TAB3 and promoting subsequent TAK1/MAP3K7 activation (PubMed:36593296).
Required for proper lipid homeostasis (PubMed:37119330).
Component of a VCP/p97-AMFR/gp78 complex that participates in the final step of endoplasmic reticulum-associated degradation (ERAD) (PubMed:10456327, PubMed:11724934, PubMed:19103148, PubMed:24424410).
The VCP/p97-AMFR/gp78 complex is involved in the sterol-accelerated ERAD degradation of HMGCR through binding to the HMGCR-INSIG1 complex at the ER membrane (PubMed:16168377, PubMed:22143767).
In addition, interaction of AMFR with AUP1 facilitates interaction of AMFR with ubiquitin-conjugating enzyme UBE2G2 and ubiquitin ligase RNF139, leading to sterol-induced HMGCR ubiquitination (PubMed:23223569).
The ubiquitinated HMGCR is then released from the ER into the cytosol for subsequent destruction (PubMed:16168377, PubMed:22143767, PubMed:23223569).
In addition to ubiquitination on lysine residues, catalyzes ubiquitination on cysteine residues: together with INSIG1, mediates polyubiquitination of SOAT2/ACAT2 at 'Cys-277', leading to its degradation when the lipid levels are low (PubMed:28604676).
Catalyzes ubiquitination and subsequent degradation of INSIG1 when cells are depleted of sterols (PubMed:17043353).
Mediates polyubiquitination of INSIG2 at 'Cys-215' in some tissues, leading to its degradation (PubMed:31953408).
Also regulates ERAD through the ubiquitination of UBL4A a component of the BAG6/BAT3 complex (PubMed:21636303).
Also acts as a scaffold protein to assemble a complex that couples ubiquitination, retranslocation and deglycosylation (PubMed:21636303).
Mediates tumor invasion and metastasis as a receptor for the GPI/autocrine motility factor (PubMed:10456327).
In association with LMBR1L and UBAC2, negatively regulates the canonical Wnt signaling pathway in the lymphocytes by promoting the ubiquitin-mediated degradation of CTNNB1 and Wnt receptors FZD6 and LRP6 (PubMed:31073040).
Regulates NF-kappa-B and MAPK signaling pathways by mediating 'Lys-27'-linked polyubiquitination of TAB3 and promoting subsequent TAK1/MAP3K7 activation (PubMed:36593296).
Required for proper lipid homeostasis (PubMed:37119330).
Catalytic activity
Pathway
Protein modification; protein ubiquitination.
GO annotations
Keywords
- Molecular function
- Biological process
- Ligand
Enzyme and pathway databases
Protein family/group databases
Names & Taxonomy
Protein names
- Recommended nameE3 ubiquitin-protein ligase AMFR
- 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 accessionQ9UKV5
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Endoplasmic reticulum membrane ; Multi-pass membrane protein
Note: Palmitoylation promotes localization to the peripheral endoplasmic reticulum.
Features
Showing features for transmembrane.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Transmembrane | 82-102 | Helical | ||||
Sequence: LFVWVLVNTACCVLMLVAKLI | ||||||
Transmembrane | 122-142 | Helical | ||||
Sequence: FWNFIFYKFIFIFGVLNVQTV | ||||||
Transmembrane | 145-165 | Helical | ||||
Sequence: VVMWCLWFAGLVFLHLMVQLC | ||||||
Transmembrane | 186-206 | Helical | ||||
Sequence: VLSLLVAMLLSCCGLAAVCSI | ||||||
Transmembrane | 215-235 | Helical | ||||
Sequence: TLAFMAAESLLVTVRTAHVIL | ||||||
Transmembrane | 276-296 | Helical | ||||
Sequence: HIHMLLFGNIWLSMASLVIFM | ||||||
Transmembrane | 429-449 | Helical | ||||
Sequence: IASWLPSFSVEVMHTTNILGI |
Keywords
- Cellular component
Disease & Variants
Involvement in disease
Spastic paraplegia 89, autosomal recessive (SPG89)
- Note
- DescriptionA form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or weakness and stiffness may spread to other parts of the body. SPG89 affected individuals show delayed motor development, abnormal spastic gait, and hyperreflexia of the lower limbs. Some patients may have mildly impaired intellectual development or learning difficulties. SPG89 disease onset is in the first years of life.
- See alsoMIM:620379
Natural variants in SPG89
Variant ID | Position(s) | Change | Description | |
---|---|---|---|---|
VAR_088630 | 85-643 | missing | in SPG89; pathogenic | |
VAR_088631 | 123-643 | missing | in SPG89; pathogenic | |
VAR_088632 | 356-643 | missing | in SPG89; likely pathogenic | |
VAR_088633 | 364-643 | missing | in SPG89; likely pathogenic |
Features
Showing features for natural variant, mutagenesis.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Natural variant | VAR_088630 | 85-643 | in SPG89; pathogenic | |||
Sequence: Missing | ||||||
Natural variant | VAR_088631 | 123-643 | in SPG89; pathogenic | |||
Sequence: Missing | ||||||
Mutagenesis | 341-344 | Decreased palmitoylation. | ||||
Sequence: CAIC → AAIA | ||||||
Mutagenesis | 346 | Abolished binding to TAB3. | ||||
Sequence: D → A | ||||||
Mutagenesis | 356 | Decreased palmitoylation. No degradation of HMGCR. | ||||
Sequence: C → A | ||||||
Natural variant | VAR_088632 | 356-643 | in SPG89; likely pathogenic | |||
Sequence: Missing | ||||||
Mutagenesis | 364 | Decreased palmitoylation. | ||||
Sequence: C → A | ||||||
Natural variant | VAR_088633 | 364-643 | in SPG89; likely pathogenic | |||
Sequence: Missing | ||||||
Mutagenesis | 375-378 | Decreased palmitoylation. | ||||
Sequence: CPTC → APTA | ||||||
Mutagenesis | 379 | Abolished binding to TAB3. | ||||
Sequence: R → A | ||||||
Natural variant | VAR_035790 | 605 | in a breast cancer sample; somatic mutation; dbSNP:rs373191257 | |||
Sequence: D → V |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 617 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, modified residue (large scale data), modified residue.
Type | ID | Position(s) | Source | Description | |||
---|---|---|---|---|---|---|---|
Chain | PRO_0000064579 | 1-643 | UniProt | E3 ubiquitin-protein ligase AMFR | |||
Sequence: MPLLFLERFPWPSLRTYTGLSGLALLGTIISAYRALSQPEAGPGEPDQLTASLQPEPPAPARPSAGGPRARDVAQYLLSDSLFVWVLVNTACCVLMLVAKLIQCIVFGPLRVSERQHLKDKFWNFIFYKFIFIFGVLNVQTVEEVVMWCLWFAGLVFLHLMVQLCKDRFEYLSFSPTTPMSSHGRVLSLLVAMLLSCCGLAAVCSITGYTHGMHTLAFMAAESLLVTVRTAHVILRYVIHLWDLNHEGTWEGKGTYVYYTDFVMELTLLSLDLMHHIHMLLFGNIWLSMASLVIFMQLRYLFHEVQRRIRRHKNYLRVVGNMEARFAVATPEELAVNNDDCAICWDSMQAARKLPCGHLFHNSCLRSWLEQDTSCPTCRMSLNIADNNRVREEHQGENLDENLVPVAAAEGRPRLNQHNHFFHFDGSRIASWLPSFSVEVMHTTNILGITQASNSQLNAMAHQIQEMFPQVPYHLVLQDLQLTRSVEITTDNILEGRIQVPFPTQRSDSIRPALNSPVERPSSDQEEGETSAQTERVPLDLSPRLEETLDFGEVEVEPSEVEDFEARGSRFSKSADERQRMLVQRKDELLQQARKRFLNKSSEDDAASESFLPSEGASSDPVTLRRRMLAAAAERRLQKQQTS | |||||||
Modified residue (large scale data) | 509 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 516 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 516 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 522 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 523 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 523 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 542 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 542 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 548 | PRIDE | Phosphothreonine | ||||
Sequence: T |
Post-translational modification
Palmitoylation of the RING-type zing finger by ZDHHC6 promotes localization to the peripheral endoplasmic reticulum.
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Tissue specificity
Widely expressed.
Gene expression databases
Organism-specific databases
Interaction
Subunit
Interacts with RNF5 (By similarity).
Also forms an ERAD complex containing VCP/p97, NGLY1; PSMC1; SAKS1 and RAD23B required for coupling retrotranslocation, ubiquitination and deglycosylation (By similarity).
Interacts with DERL1 (PubMed:16186510).
Interacts (through a region distinct from the RING finger) with UBE2G2/UBC7 (PubMed:11724934).
Component of the VCP/p97-AMFR/gp78 complex that enhances VCP/p97 binding to polyubiquitinated proteins for their degradation by the endoplasmic reticulum-associated degradation (ERAD) pathway (By similarity).
Interacts (via the VIM) with VCP/p97 (PubMed:16168377, PubMed:16186510).
Interacts (via its membrane domain) with INSIG1; the interaction initiates the sterol-mediated ubiquitination and degradation of HMGCR by the ERAD pathway (PubMed:16168377, PubMed:22143767).
Interacts with AUP1, UBE2G2 and RNF139/TRC8; interaction with AUP1 facilitates interaction of AMFR with ubiquitin-conjugating enzyme UBE2G2 and ubiquitin ligase RNF139, leading to sterol-induced ubiquitination of HMGCR and its subsequent proteasomal degradation (PubMed:23223569).
Interacts with BAG6 (PubMed:21636303).
Interacts with USP13 (via UBA 2 domain); the interaction is direct (PubMed:24424410).
Interacts with LMBR1L (PubMed:31073040).
Interacts with UBAC2 and CTNNB1 (By similarity).
Interacts with C18orf32 (PubMed:29275994).
Also forms an ERAD complex containing VCP/p97, NGLY1; PSMC1; SAKS1 and RAD23B required for coupling retrotranslocation, ubiquitination and deglycosylation (By similarity).
Interacts with DERL1 (PubMed:16186510).
Interacts (through a region distinct from the RING finger) with UBE2G2/UBC7 (PubMed:11724934).
Component of the VCP/p97-AMFR/gp78 complex that enhances VCP/p97 binding to polyubiquitinated proteins for their degradation by the endoplasmic reticulum-associated degradation (ERAD) pathway (By similarity).
Interacts (via the VIM) with VCP/p97 (PubMed:16168377, PubMed:16186510).
Interacts (via its membrane domain) with INSIG1; the interaction initiates the sterol-mediated ubiquitination and degradation of HMGCR by the ERAD pathway (PubMed:16168377, PubMed:22143767).
Interacts with AUP1, UBE2G2 and RNF139/TRC8; interaction with AUP1 facilitates interaction of AMFR with ubiquitin-conjugating enzyme UBE2G2 and ubiquitin ligase RNF139, leading to sterol-induced ubiquitination of HMGCR and its subsequent proteasomal degradation (PubMed:23223569).
Interacts with BAG6 (PubMed:21636303).
Interacts with USP13 (via UBA 2 domain); the interaction is direct (PubMed:24424410).
Interacts with LMBR1L (PubMed:31073040).
Interacts with UBAC2 and CTNNB1 (By similarity).
Interacts with C18orf32 (PubMed:29275994).
(Microbial infection) Interacts with Staphylococcus aureus HIgB; this interaction regulates AMFR-mediated inflammation by promoting TAB3 ubiquitination to promote TAB3-TAK1 complex formation.
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
BINARY | Q9UKV5 | AMFR Q9UKV5 | 11 | EBI-1046367, EBI-1046367 | |
BINARY | Q9UKV5 | ERLIN1 O75477 | 2 | EBI-1046367, EBI-359299 | |
BINARY | Q9UKV5 | ERLIN2 O94905 | 10 | EBI-1046367, EBI-4400770 | |
BINARY | Q9UKV5 | INSIG1 O15503 | 2 | EBI-1046367, EBI-6252425 | |
BINARY | Q9UKV5 | TMUB1 Q9BVT8 | 2 | EBI-1046367, EBI-11425701 | |
BINARY | Q9UKV5 | UBE2G2 P60604 | 21 | EBI-1046367, EBI-1051028 | |
XENO | Q9UKV5 | Ube2g2 P60605 | 10 | EBI-1046367, EBI-9108745 | |
BINARY | Q9UKV5 | VCP P55072 | 12 | EBI-1046367, EBI-355164 |
Protein-protein interaction databases
Miscellaneous
Structure
Family & Domains
Features
Showing features for region, zinc finger, domain, compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 39-67 | Disordered | ||||
Sequence: PEAGPGEPDQLTASLQPEPPAPARPSAGG | ||||||
Zinc finger | 341-379 | RING-type | ||||
Sequence: CAICWDSMQAARKLPCGHLFHNSCLRSWLEQDTSCPTCR | ||||||
Domain | 456-498 | CUE | ||||
Sequence: QLNAMAHQIQEMFPQVPYHLVLQDLQLTRSVEITTDNILEGRI | ||||||
Compositional bias | 504-521 | Polar residues | ||||
Sequence: TQRSDSIRPALNSPVERP | ||||||
Region | 504-579 | Disordered | ||||
Sequence: TQRSDSIRPALNSPVERPSSDQEEGETSAQTERVPLDLSPRLEETLDFGEVEVEPSEVEDFEARGSRFSKSADERQ | ||||||
Compositional bias | 561-579 | Basic and acidic residues | ||||
Sequence: VEDFEARGSRFSKSADERQ | ||||||
Region | 596-624 | Disordered | ||||
Sequence: RFLNKSSEDDAASESFLPSEGASSDPVTL | ||||||
Region | 622-640 | VCP/p97-interacting motif (VIM) | ||||
Sequence: VTLRRRMLAAAAERRLQKQ |
Domain
The CUE domain is required for recognition of misfolded proteins such as mutant CFTR.
The VCP/p97-interacting motif (VIM) is sufficient for binding VCP/p97 to form a complex capable of transferring VCP/p97 from the cytosol to microsomes.
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Length643
- Mass (Da)72,996
- Last updated2003-06-01 v2
- Checksum8782324609C0E62A
Computationally mapped potential isoform sequences
There are 4 potential isoforms mapped to this entry
Sequence caution
Features
Showing features for sequence conflict, compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Sequence conflict | 406 | in Ref. 3; AAA79362 | ||||
Sequence: V → D | ||||||
Sequence conflict | 491 | in Ref. 3; AAA79362 | ||||
Sequence: D → V | ||||||
Sequence conflict | 500 | in Ref. 3; AAA79362 | ||||
Sequence: V → L | ||||||
Compositional bias | 504-521 | Polar residues | ||||
Sequence: TQRSDSIRPALNSPVERP | ||||||
Compositional bias | 561-579 | Basic and acidic residues | ||||
Sequence: VEDFEARGSRFSKSADERQ | ||||||
Sequence conflict | 614 | in Ref. 1; AAD56722 | ||||
Sequence: S → L |
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AF124145 EMBL· GenBank· DDBJ | AAD56722.1 EMBL· GenBank· DDBJ | mRNA | ||
BC069197 EMBL· GenBank· DDBJ | AAH69197.1 EMBL· GenBank· DDBJ | mRNA | ||
L35233 EMBL· GenBank· DDBJ | AAA79362.1 EMBL· GenBank· DDBJ | mRNA | Frameshift | |
M63175 EMBL· GenBank· DDBJ | AAA36671.1 EMBL· GenBank· DDBJ | mRNA | Sequence problems. |