Structure of a BAG6 (Bcl-2-associated athanogene 6)-Ubl4a (ubiquitin-like protein 4a) complex reveals a novel binding interface that functions in tail-anchored protein biogenesis

J Biol Chem. 2015 Apr 10;290(15):9387-98. doi: 10.1074/jbc.M114.631804. Epub 2015 Feb 20.


BAG6 is an essential protein that functions in two distinct biological pathways, ubiquitin-mediated protein degradation of defective polypeptides and tail-anchored (TA) transmembrane protein biogenesis in mammals, although its structural and functional properties remain unknown. We solved a crystal structure of the C-terminal heterodimerization domains of BAG6 and Ubl4a and characterized their interaction biochemically. Unexpectedly, the specificity and structure of the C terminus of BAG6, which was previously classified as a BAG domain, were completely distinct from those of the canonical BAG domain. Furthermore, the tight association of BAG6 and Ubl4a resulted in modulation of Ubl4a protein stability in cells. Therefore, we propose to designate the Ubl4a-binding region of BAG6 as the novel BAG-similar (BAGS) domain. The structure of Ubl4a, which interacts with BAG6, is similar to the yeast homologue Get5, which forms a homodimer. These observations indicate that the BAGS domain of BAG6 promotes the TA protein biogenesis pathway in mammals by the interaction with Ubl4a.

Keywords: Membrane Protein; Protein Assembly; Small-angle X-ray Scattering (SAXS); Tail Anchor; Ubiquitin; X-ray Crystallography.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Crystallography, X-Ray
  • HeLa Cells
  • Humans
  • Immunoblotting
  • Membrane Proteins / chemistry
  • Membrane Proteins / metabolism
  • Mice
  • Models, Molecular
  • Molecular Chaperones / chemistry*
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism
  • Molecular Sequence Data
  • Multiprotein Complexes / chemistry*
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism
  • Mutation
  • NIH 3T3 Cells
  • Nuclear Proteins / chemistry*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Protein Binding
  • Protein Structure, Secondary*
  • Protein Structure, Tertiary*
  • Scattering, Small Angle
  • Sequence Homology, Amino Acid
  • Ubiquitins / chemistry*
  • Ubiquitins / genetics
  • Ubiquitins / metabolism
  • X-Ray Diffraction


  • Bag6 protein, mouse
  • Membrane Proteins
  • Molecular Chaperones
  • Multiprotein Complexes
  • Nuclear Proteins
  • Ubiquitins
  • Ubl4a protein, mouse

Associated data

  • PDB/4X86