Abstract
Hsc70 is a conserved ATP-dependent molecular chaperone, which utilizes the energy of ATP hydrolysis to alter the folding state of its client proteins. In contrast to the Hsc70 systems of bacteria, yeast and humans, the Hsc70 system of C. elegans (CeHsc70) has not been studied to date.We find that CeHsc70 is characterized by a high ATP turnover rate and limited by post-hydrolysis nucleotide exchange. This rate-limiting step is defined by the helical lid domain at the C-terminus. A certain truncation in this domain (CeHsc70-Δ545) reduces the turnover rate and renders the hydrolysis step rate-limiting. The helical lid domain also affects cofactor affinities as the lidless mutant CeHsc70-Δ512 binds more strongly to DNJ-13, forming large protein complexes in the presence of ATP. Despite preserving the ability to hydrolyze ATP and interact with its cofactors DNJ-13 and BAG-1, the truncation of the helical lid domain leads to the loss of all protein folding activity, highlighting the requirement of this domain for the functionality of the nematode's Hsc70 protein.
Highlights
Hsc70 and its heat-shock inducible homolog Hsp70 are ATPdependent molecular chaperones which bind unfolded proteins [1]
We analyzed the Hsc70 system of C. elegans by utilizing truncation mutants in the C-terminal lid domain
CeHsc70 apparently more closely resembles CeHsc70-D512, as its turnover is limited by nucleotide release
Summary
Hsc and its heat-shock inducible homolog Hsp are ATPdependent molecular chaperones which bind unfolded proteins [1]. They participate in various cellular processes as diverse as protein de novo folding, protein translocation across organelle membranes and uncoating of clathrin-coated vesicles [2,3,4,5,6,7,8]. Like the yeast proteins Ssb, Ssb and Ssz, reside at the ribosome as part of the ribosomeassociated complex (RAC), while others, such as Hsc70s and the heat-inducible Hsp70s are assumed to be diffusible factors in the cytosol. The RNAi-mediated knockdown of CeHsc has dramatic consequences, leading to increased protein aggregation [13] and arrested development at early larval stages [14,15], confirming that essential and non-redundant cellular functions are performed by this homolog of Hsc
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