Caught in the middle: the role of Bag3 in disease

Abstract

Bag3 is a Bag family co-chaperone that regulates the ATPase activity of Hsp70 (heat-shock protein 70) chaperones. Recent studies have demonstrated that Bag3 can initiate macroautophagy in co-operation with small heat-shock protein HspB8. In this issue of the Biochemical Journal, Fuchs and co-workers have discovered the IPV motif in Bag3 that is necessary for binding to HspB8. The authors have also identified HspB6 as a new binding partner for Bag3 and characterized further the binding of both HspB8 and HspB6 in Bag3-mediated clearance of aggregated polyglutamine-containing protein Htt43Q (huntingtin exon 1 fragment with 43 CAG repeats). It is clear from recent identification of a Bag3 mutation that causes a form of muscular dystrophy that the full function of Bag3 in disease is not clear. We will apply the findings of Fuchs et al. in this issue to reconcile the phenotypes of Bag3 homologue knockouts with the emerging role of Bag3 in autophagy.

Figure 1. Human Bag3 protein domains and their interactions

The two newly identified IPV motifs are the site for binding for the complex formation of Bag3 with HspB6 and HspB8. Both sHsps interact through their hydrophobic groove to form the Bag3 complex. Flanking the IPV motifs are the WW domain, consisting of two tryptophan residues spaced 20–22 amino acids apart for which no function has been identified, and the proline-rich (PXXP) region documented to bind proteins containing an SH3 motif. The BAG domain consists of three anti-parallel α-helices, the last two of which bind with high affinity to the ATPase domain of Hsps 70 (Hsp70/Hsc70). Bag3 also associates with the anti-apoptotic protein Bcl-2 through its BAG domain. The C-terminal ⁵¹⁵LEAD, conserved in higher mammals, is a functional caspase recognition and cleavage site.