We showed altered expression of Hsp40s, nucleotide exchange factors (NEFs) and several TPR-domain proteins can affect prion propagation in wild type and Hsp70 mutant cells. We also identified several Hsp40 and TPR protein mutant alleles that impair or enhance prion propagation. Together our data imply that many, if not all the observed effects of co-chaperones on prions are mediated by their regulation of Hsp70 activities. In many instances the same conditions producing a significant effect on one prion have little or no effect on a different prion, pointing to a prion preference or specificity of the Hsp70/co-chaperone partners. Our recent findings are in agreement with this notion suggesting that effects on Hsp70 function underlie prion-specific effects of the co-chaperones, and we believe further work with our system will lead to identification of specific Hsp70/co-chaperone partners whose function is important for propagation properties of different prions. To this end we are using genetic and biochemical methods to characterize physical and functional interactions between the co-chaperones and Hsp70. We have purified wild type and mutant co-chaperones to homogeneity to analyze their binding specificities, enzymatic functions and ability to physically interact with Hsp70. We are assessing functional interactions between co-chaperones and Hsp70 in vitro by how they influence physical properties and propagation of amyloid, or prevent protein aggregation and refold denatured proteins.
| Xue, You-Lin; Wang, Hao; Riedy, Michael et al. (2018) Molecular dynamics simulations of Hsp40 J-domain mutants identifies disruption of the critical HPD-motif as the key factor for impaired curing in vivo of the yeast prion [URE3]. J Biomol Struct Dyn 36:1764-1775 |
| Sharma, Deepak; Stanley, Robert F; Masison, Daniel C (2009) Curing of yeast [URE3] prion by the Hsp40 cochaperone Ydj1p is mediated by Hsp70. Genetics 181:129-37 |
