The mechanical roles of chaperones.

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Protein folding under force is an integral source of generating mechanical energy in various cellular processes, ranging from protein translation to degradation. Although chaperones are well known to interact with proteins under mechanical force, how they respond to force and control cellular energetics remains unknown. To address this question, we introduce novel real-time covalent-magnetic-tweezers technology to apply physiological force pulses on client proteins, keeping the chaperones unperturbed. Interestingly we found that chaperones, under physiological constraints, can work in a different way than its previously known function. For example, TF and DsbA like tunnel associated chaperones, otherwise acting as a holdase in absence of force, accelerate the protein folding under force. Similarly, a well described foldase Hsp70 complex (DnaKJE) fails to accelerate the folding process under mechanical constraints. However, individual components of this complex (DnaJ, DnaK) showed similar holdase properties, both in the absence and presence of force. Thus, our study reveals a novel concept of a spatially distributed mechanical behavior of chaperones, i.e. tunnel-associated chaperones can accelerate the folding of translocating polypeptides and thus reduce the overall energy required for the translation or translocation process, while their cytosolic counterparts (PDI, Thioredoxin or DnaKJE) fail to do so. This behavior may have evolved to minimize the energetic cost of various biological processes.