Bag6 complex contains a minimal tail-anchor-targeting module and a mock BAG domain

Proc Natl Acad Sci U S A. 2015 Jan 6;112(1):106-11. doi: 10.1073/pnas.1402745112. Epub 2014 Dec 22.

Abstract

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 α to TRC40. These findings provide structural insight into the complex network of proteins coordinated by Bag6.

Keywords: Bat3; GET pathway; Scythe; X-ray crystallography; tail-anchored proteins.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Cell Nucleus / metabolism
  • Crystallography, X-Ray
  • Humans
  • Models, Biological
  • Molecular Chaperones / chemistry*
  • Molecular Chaperones / metabolism*
  • Molecular Sequence Data
  • Nuclear Localization Signals
  • Protein Binding
  • Protein Multimerization
  • Protein Structure, Tertiary
  • Protein Transport
  • Structural Homology, Protein
  • Structure-Activity Relationship
  • Two-Hybrid System Techniques
  • Ubiquitins / chemistry
  • Ubiquitins / metabolism*

Substances

  • BAG6 protein, human
  • Molecular Chaperones
  • Nuclear Localization Signals
  • Trc35 protein, human
  • Ubiquitins
  • Ubl4A protein, human

Associated data

  • PDB/4WWR