Why do we need so many proteins? A physical insight into the collaboration of Hsp70 and DnaJ

The Hsp70 cycle is a key element of protein homeostasis, which is essential to avoid protein aggregation and protein-related diseases. Despite many experimental observations of the interaction between Hsp70, its co-chaperone DnaJ and various substrates, little focus has been given so far to the development of general and predictive models of such interactions.

In this context, this thesis introduces different models to highlight the key features of the Hsp70/DnaJ system and provides a comprehensive description of its mechanism. We first describe different selection mechanisms and their impact in out-of-equilibrium dynamics, emphasizing the importance of the catalytic discrimination as a necessary, though not sufficient, step to ensure a fast and accurate selection. We then focus on the Hsp70 system, first by presenting an innovative model to explain the regulation mechanism of its ATPase activity and the synergistic effect of the substrate and DnaJ on this activity. We highlight how the synergistic effect can be seen as a selection step allowing Hsp70 to discriminate substrates. Finally, we examine the complete Hsp70 cycle with an emphasis on the impact of 3-body interactions and propose the existence of a regulatory mechanism for DnaJ. Our resulting model allows us to highlight the mechanisms used by Hsp70 to act on misfolded proteins.