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.
Identification of the key structural motifs involved in HspB8/HspB6-Bag3 interaction / Fuchs, M; Poirier, Dj; Seguin, Sj; Lambert, H; Carra, Serena; Charette, Sj; Landry, J.. - In: BIOCHEMICAL JOURNAL. - ISSN 0264-6021. - ELETTRONICO. - 425(1)(2009), pp. 245-255. [10.1042/BJ20090907]
|Data di pubblicazione:||2009|
|Titolo:||Identification of the key structural motifs involved in HspB8/HspB6-Bag3 interaction.|
|Autore/i:||Fuchs, M; Poirier, Dj; Seguin, Sj; Lambert, H; Carra, Serena; Charette, Sj; Landry, J.|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1042/BJ20090907|
|Codice identificativo ISI:||WOS:000273585000024|
|Codice identificativo Scopus:||2-s2.0-72449141635|
|Codice identificativo Pubmed:||19845507|
|Citazione:||Identification of the key structural motifs involved in HspB8/HspB6-Bag3 interaction / Fuchs, M; Poirier, Dj; Seguin, Sj; Lambert, H; Carra, Serena; Charette, Sj; Landry, J.. - In: BIOCHEMICAL JOURNAL. - ISSN 0264-6021. - ELETTRONICO. - 425(1)(2009), pp. 245-255. [10.1042/BJ20090907]|
|Tipologia||Articolo su rivista|
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