Abstract
Hsc70 is known to be involved in clathrin-mediated endocytosis (CME) by which cells take up various extracellular materials. More specifically, this protein promotes the disassembly of clathrin-coated vesicles (CCVs) by directly binding to clathrin during CME. As the ATPase activity of Hsc70 is required for its association with clathrin, we have investigated the effect of an inhibitor (apoptozole, Az) of an ATPase domain of Hsc70 on CME. The results of biochemical studies show that Az binds to Hsc70 and Hsp70 without binding to other types of heat shock proteins. Structure-activity relationship studies provide information on the structural features responsible for the inhibition of the ATPase activity of Hsc70. The results obtained from cell experiments reveal that Az disrupts the interaction of Hsc70 with clathrin in cells, thereby leading to the accumulation of transferrin in CCVs and suppression of release of free Fe(3+) from CCVs during transferrin receptor-mediated endocytosis.
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