期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：1
页码：106-111
DOI：10.1073/pnas.1402745112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceQuality control of proteins is critical to cellular homeostasis. The BCL2-associated athanogene cochaperone 6 (Bag6) complex, which contains Bag6, transmembrane domain recognition complex 35 (TRC35), and ubiquitin-like 4A (Ubl4A), plays an essential role in targeting transmembrane domains either to the endoplasmic reticulum or degradation. Bag6 is a central hub for numerous activities, functionally linked to an array of cellular pathways, from immunoregulation to apoptosis. Here we define the molecular architecture of this heterotrimer, revealing distinct binding sites on Bag6 for TRC35 and Ubl4A. The truncated Bag6 complex defined in this study is sufficient to facilitate substrate transfer from small glutamine-rich tetratricopeptide repeat-containing protein (SGTA) to TCR40. In addition, structural and biochemical characterization of the BAG domain of Bag6 demonstrate that it is not a canonical BAG domain. BCL2-associated athanogene cochaperone 6 (Bag6) plays a central role in cellular homeostasis in a diverse array of processes and is part of the heterotrimeric Bag6 complex, which also includes ubiquitin-like 4A (Ubl4A) and transmembrane domain recognition complex 35 (TRC35). This complex recently has been shown to be important in the TRC pathway, the mislocalized protein degradation pathway, and the endoplasmic reticulum-associated degradation pathway. Here we define the architecture of the Bag6 complex, demonstrating that both TRC35 and Ubl4A have distinct C-terminal binding sites on Bag6 defining a minimal Bag6 complex. A crystal structure of the Bag6-Ubl4A dimer demonstrates that Bag6-BAG is not a canonical BAG domain, and this finding is substantiated biochemically. Remarkably, the minimal Bag6 complex defined here facilitates tail-anchored substrate transfer from small glutamine-rich tetratricopeptide repeat-containing protein to TRC40. These findings provide structural insight into the complex network of proteins coordinated by Bag6.
