Recombinant Human E3 ubiquitin-protein ligase AMFR (AMFR) Protein

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)

Subcellular Location

Endoplasmic reticulum membrane (Multi-pass membrane protein)

Disease Association

Spastic paraplegia 89, autosomal recessive (SPG89) : A 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. [The disease is caused by variants affecting the gene represented in this entry]

Tissue Specificity

Widely expressed

Subunit

(Microbial infection) Interacts with Staphylococcus aureus HIgB; this interaction regulates AMFR-mediated inflammation by promoting TAB3 ubiquitination to promote TAB3-TAK1 complex formation

Pathway

Protein modification; protein ubiquitination

• Shimizu K. et al. The autocrine motility factor receptor gene encodes a novel type of seven transmembrane protein. — FEBS Lett. (1999)
• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). — Genome Res. (2004)
• Huang B. et al. Identification of an upstream region that controls the transcription of the human autocrine motility factor receptor. — Biochem. Biophys. Res. Commun. (1995)
• Watanabe H. et al. Purification of human tumor cell autocrine motility factor and molecular cloning of its receptor. — J. Biol. Chem. (1991)
• Fang S. et al. The tumor autocrine motility factor receptor, gp78, is a ubiquitin protein ligase implicated in degradation from the endoplasmic reticulum. — Proc. Natl. Acad. Sci. U.S.A. (2001)
• Liang J.S. et al. Overexpression of the tumor autocrine motility factor receptor, gp78, a ubiquitin protein ligase (E3), results in increased ubiquitinylation and decreased secretion of apolipoprotein B100 in Hep G2 cells. — J. Biol. Chem. (2003)
• Song B.L. et al. Gp78, a membrane-anchored ubiquitin ligase, associates with Insig-1 and couples sterol-regulated ubiquitination to degradation of HMG CoA reductase. — Mol. Cell (2005)
• Ye Y. et al. Recruitment of the p97 ATPase and ubiquitin ligases to the site of retrotranslocation at the endoplasmic reticulum membrane. — Proc. Natl. Acad. Sci. U.S.A. (2005)