Fig. 8: Schematic diagram depicting possible mechanism of LGMDD1 mutants and their effects on the Hsp70 ATPase cycle, as well as proposed therapeutic intervention.

a Cartoon depicting possible mechanistic insights as to how LGMDD1 G/F domain mutants delay or inhibit the Hsp70 ATPase cycle. The dashed red arrows indicate inhibition. Mutants were inefficient in terms of both homo and hetero-dimerization and that may be related to their reduced ability to assist Hsp70 in protein folding. In the first half of the Hsp70 ATPase cycle, LGMDD1 mutants were incompetent in their ability to bind specific substrate conformers and Hsp70 (black dashed arrows), which delays the downstream processing of the substrate through Hsp70-ATPase cycle. This inhibition could negatively impact Hsp70-mediated ATP-hydrolysis. b Possible therapeutic route. In the second half of the cycle, modulation of NEF inhibit the binding and exchange of nucleotide, which delay the downstream process of substrate release in the cycle. However, this delay led to positive consequences in terms of yeast prion propagation (green arrow represents restoration of normal function). Thus, altering the balance between the two halves of the Hsp70-ATPase cycle may provide one route for therapeutic intervention for these types of diseases.