Force-regulated chaperone activity of BiP/ERdj3 is opposite to their homologs DnaK/DnaJ: explained by strain energy

Abstract

Polypeptide chains experiences mechanical tension while translocating through cellular tunnel. In this scenario, interaction of tunnel-associated chaperones with the emerging polypeptide occurs under force; however, this force-regulated chaperone behaviour is not fully understood. We studied the mechanical chaperone activity of two tunnel-associated chaperones BiP and ERdj3 both in the absence and presence of force; and compared to their respective cytoplasmic homologs DnaK and DnaJ. We found that BiP/ERdj3 shows strong foldase activity under force; whereas their cytoplasmic homolog DnaK/DnaJ behave as holdase. Importantly, these tunnel-associated chaperones (BiP/ERdj3) revert to holdase in the absence of force, suggesting that mechanical chaperone activity differs depending on the presence or absence of force. This tunnel-associated chaperone-driven folding event generates additional mechanical energy of up to 54 zJ that could help protein translocation. The mechanical-chaperone behaviour can be explained by strain theory: chaperones with higher intrinsic deformability function as mechanical foldase (BiP, ERdj3), while chaperones with lower intrinsic deformability act as holdase (DnaK and DnaJ). Our study thus unveils the underlying mechanism of mechanically regulated chaperoning activity and provides a novel mechanism of co-translocational protein folding.