Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026850 (muscular dystrophy)
 5,870 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The molecular chaperone HspB8 [Hsp (heat-shock protein) B8] is member of the B-group of Hsps. These proteins bind to unfolded or misfolded proteins and protect them from aggregation. HspB8 has been reported to form a stable molecular complex with the chaperone cohort protein Bag3 (Bcl-2-associated athanogene 3). In the present study we identify the binding regions in HspB8 and Bag3 crucial for their interaction. We present evidence that HspB8 binds to Bag3 through the hydrophobic groove formed by its strands beta4 and beta8, a region previously known to be responsible for the formation and stability of higher-order oligomers of many sHsps (small Hsps). Moreover, we demonstrate that two conserved IPV (Ile-Pro-Val) motifs in Bag3 mediate its binding to HspB8 and that deletion of these motifs suppresses HspB8 chaperone activity towards mutant Htt43Q (huntingtin exon 1 fragment with 43 CAG repeats). In addition, we show that Bag3 can bind to the molecular chaperone HspB6. The interaction between HspB6 and Bag3 requires the same regions that are involved in the HspB8-Bag3 association and HspB6-Bag3 promotes clearance of aggregated Htt43Q. Our findings suggest that the co-chaperone Bag3 might prevent the accumulation of denatured proteins by regulating sHsp activity and by targeting their substrate proteins for degradation. Interestingly, a mutation in one of Bag3 IPV motifs has recently been associated with the development of severe dominant childhood muscular dystrophy, suggesting a possible important physiological role for HspB-Bag3 complexes in this disease.
 ...
PMID:Identification of the key structural motifs involved in HspB8/HspB6-Bag3 interaction. 2000 57

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.
 ...
PMID:Caught in the middle: the role of Bag3 in disease. 1984 7