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The structural basis for regulation of the nucleo-cytoplasmic distribution of Bag6 by TRC35

The metazoan protein BCL2-associated athanogene cochaperone 6 (Bag6) forms a hetero-trimeric complex with ubiquitin-like 4A (Ubl4A) and transmembrane domain recognition complex 35 (TRC35). This Bag6 complex is involved in tail-anchored protein targeting and various protein quality control pathways in the cytosol as well as regulating transcription and histone methylation in the nucleus. Here we present a crystal structure of Bag6 and its cytoplasmic retention factor TRC35, revealing that TRC35 is remarkably conserved throughout opisthokont lineage except at the C-terminal Bag6-binding groove, which evolved to accommodate a novel metazoan factor Bag6. Remarkably, while TRC35 and its fungal homolog guided entry of tail-anchored protein 4 (Get4) utilize a conserved hydrophobic patch to bind their respective C-terminal binding partners Bag6 and Get5, Bag6 wraps around TRC35 on the opposite face relative to the Get4-5 interface. We further demonstrate that the residues involved in TRC35 binding are not only critical for occluding the Bag6 nuclear localization sequence from karyopherin α binding to retain Bag6 in the cytosol, but also for preventing TRC35 from succumbing to RNF126-mediated ubiquitylation and degradation. The results provide a mechanism for regulation of Bag6 nuclear localization and the functional integrity of the Bag6 complex in the cytosol.