The Hsp70 and JDP proteins: Structure-function perspective on molecular chaperone activity.

Proteins are the most structurally diverse cellular biomolecules that act as molecular machines driving essential activities of all living organisms. To be functional, most of the proteins need to fold into a specific three-dimensional structure, which on one hand should be stable enough to oppose disruptive conditions and on the other hand flexible enough to allow conformational dynamics necessary for their biological functions. This compromise between stability and dynamics makes proteins susceptible to stress-induced misfolding and aggregation. Moreover, the folding process itself is intrinsically prone to conformational errors. Molecular chaperones are proteins that mitigate folding defects and maintain the structural integrity of the cellular proteome. Promiscuous Hsp70 chaperones are central to these processes and their activity depends on the interaction with obligatory J-domain protein (JDP) partners. In this review, we discuss structural aspects of Hsp70s, JDPs, and their interaction in the context of biological activities.

Remdesivir triphosphate blocks DNA synthesis and increases exonucleolysis by the replicative mitochondrial DNA polymerase, Pol γ.

The COVID-19 pandemic prompted the FDA to authorize a new nucleoside analogue, remdesivir, for emergency use in affected individuals. We examined the effects of its active metabolite, remdesivir triphosphate (RTP), on the activity of the replicative mitochondrial DNA polymerase, Pol γ. We found that while RTP is not incorporated by Pol γ into a nascent DNA strand, it remains associated with the enzyme impeding its synthetic activity and stimulating exonucleolysis. In spite of that, we found no evidence for deleterious effects of remdesivir treatment on the integrity of the mitochondrial genome in human cells in culture.