title: A ubiquitin-like domain recruits an oligomeric chaperone to a retrotranslocation complex in endoplasmic reticulum-associated degradation.
abstract: The Bag6-Ubl4A-Trc35 complex is a multifunctional chaperone that regulates various cellular processes. The diverse functions of Bag6 are supported by its ubiquitous localization to the cytoplasm, the nucleus, and membranes of the endoplasmic reticulum (ER) in cells. In ER-associated degradation (ERAD) pathways, Bag6 can interact with the membrane-associated ubiquitin ligase gp78 via its ubiquitin-like (UBL) domain, but the relative low affinity of this interaction does not reconcile with the fact that a fraction of Bag6 is tightly bound to the membranes. Here, we demonstrate that the UBL domain of Bag6 is required for interaction with the ER membranes. We find that in addition to gp78, the Bag6 UBL domain also binds a UBL-binding motif in UbxD8, an essential component of the gp78 ubiquitinating machinery. Importantly, Bag6 contains a proline-rich (PR) domain termed PDP (Proline rich-DUF3587-Proline rich) that forms homo-oligomer, allowing the UBL domain to form multivalent interactions with gp78 and UbxD8, which are essential for recruitment of Bag6 to the ER membrane. Furthermore, the PR domain comprises largely intrinsically disordered segments, which are sufficient for interaction with an unfolded substrate. We propose that simultaneous association with multiple ERAD factors helps to anchor a disordered chaperone oligomer to the site of retrotranslocation to prevent protein aggregation in ERAD.
authors.affiliation: Laboratory of Molecular Biology, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Xu
authors.forename: Yanfen
authors.initials: Y
authors.lastname: Liu
authors.forename: Jin-gu
authors.initials: JG
authors.lastname: Lee
authors.forename: Yihong
authors.initials: Y
authors.lastname: Ye
mesh_terms: D001665:Binding Sites / Q000235:genetics; D001798:Blood Proteins / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D060746:Endoplasmic Reticulum-Associated Degradation; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D034622:RNA Interference; D060285:Receptors, Autocrine Motility Factor / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism*
chemical_list: C092009:BAG6 protein, human; D001798:Blood Proteins; C468782:FAF2 protein, human; C583269:GET4 protein, human; D008565:Membrane Proteins; D018832:Molecular Chaperones; D046912:Multiprotein Complexes; D025801:Ubiquitin; D014452:Ubiquitins; C583268:Ubl4A protein, human; C555000:AMFR protein, human; D060285:Receptors, Autocrine Motility Factor
keywords: Bag6/Bat3/Scythe; E3 Ubiquitin Ligase; ER-associated Degradation; Endoplasmic Reticulum Stress; Endoplasmic Reticulum(ER); Holdase; Molecular Chaperone; Retrotranslocation; gp78