Abstract
The J-domain co-chaperones work together with the heat shock protein 70 (HSP70) chaperone to regulate many cellular events, but the mechanism underlying the J-domain-mediated HSP70 function remains elusive. We studied the interaction between human-inducible HSP70 and Homo sapiens J-domain protein (HSJ1a), a J domain and UIM motif-containing co-chaperone. The J domain of HSJ1a shares a conserved structure with other J domains from both eukaryotic and prokaryotic species, and it mediates the interaction with and the ATPase cycle of HSP70. Our in vitro study corroborates that the N terminus of HSP70 including the ATPase domain and the substrate-binding β-subdomain is not sufficient to bind with the J domain of HSJ1a. The C-terminal helical α-subdomain of HSP70, which was considered to function as a lid of the substrate-binding domain, is crucial for binding with the J domain of HSJ1a and stimulating the ATPase activity of HSP70. These fluctuating helices are likely to contribute to a proper conformation of HSP70 for J-domain binding other than directly bind with the J domain. Our findings provide an alternative mechanism of allosteric activation for functional regulation of HSP70 by its J-domain co-chaperones.
Highlights
HSJ1a can bind with heat shock protein 70 (HSP70) to regulate many cellular events
Our findings provide an alternative mechanism of allosteric activation for functional regulation of HSP70 by its J-domain co-chaperones
The J Domain of HSJ1a Regulates the ATPase Activity of HSP70—The previous studies showed that the HSP70 proteins have a very weak basal ATPase activity, and the J-domain proteins function to stimulate their ATPase activities [24, 25]
Summary
Results: The C-terminal helices of HSP70 contribute to its interaction with HSJ1a J-domain and stimulation of ATPase activity. Significance: This finding provides an alternative mechanism of allosteric activation for functional regulation of HSP70 by its J-domain co-chaperones. The C-terminal helical ␣-subdomain of HSP70, which was considered to function as a lid of the substrate-binding domain, is crucial for binding with the J domain of HSJ1a and stimulating the ATPase activity of HSP70. Our findings provide an alternative mechanism of allosteric activation for functional regulation of HSP70 by its J-domain co-chaperones. We report that the C-terminal helical subdomain of HSP70 is essential for binding with the J domain of HSJ1a, and the specific binding is the basis for stimulating the ATPase activity of HSP70. The binding of the J domain to HSP70 may cause an allosteric activation of the ATPase domain of HSP70 through conformational fluctuation of the C-terminal subdomain and the entire HSP70 protein
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