title: SGTA recognizes a noncanonical ubiquitin-like domain in the Bag6-Ubl4A-Trc35 complex to promote endoplasmic reticulum-associated degradation.
abstract: Elimination of aberrantly folded polypeptides from the endoplasmic reticulum (ER) by the ER-associated degradation (ERAD) system promotes cell survival under stress conditions. This quality control mechanism requires movement of misfolded proteins across the ER membrane for targeting to the cytosolic proteasome, a process facilitated by a "holdase" complex, consisting of Bag6 and the cofactors Ubl4A and Trc35. This multiprotein complex also participates in several other protein quality control processes. Here, we report SGTA as a component of the Bag6 system, which cooperates with Bag6 to channel dislocated ERAD substrates that are prone to aggregation. Using nuclear magnetic resonance spectroscopy and biochemical assays, we demonstrate that SGTA contains a noncanonical ubiquitin-like-binding domain that interacts specifically with an unconventional ubiquitin-like protein/domain in Ubl4A at least in part via electrostatics. This interaction helps recruit SGTA to Bag6, enhances substrate loading to Bag6, and thus prevents the formation of nondegradable protein aggregates in ERAD.
authors.affiliation: Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Xu
authors.forename: Mengli
authors.initials: M
authors.lastname: Cai
authors.forename: Yingying
authors.initials: Y
authors.lastname: Yang
authors.forename: Lan
authors.initials: L
authors.lastname: Huang
authors.forename: Yihong
authors.initials: Y
authors.lastname: Ye
mesh_terms: D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D060746:Endoplasmic Reticulum-Associated Degradation / Q000502:physiology*; D006801:Humans; D018832:Molecular Chaperones / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019906:Nuclear Magnetic Resonance, Biomolecular; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary
chemical_list: C092009:BAG6 protein, human; D002352:Carrier Proteins; D018832:Molecular Chaperones; D046912:Multiprotein Complexes; C114575:SGTA protein, human