Investigation of Hsp90 Regulation by the Aha-type Co-chaperones: Mechanistic Insight into Two Conserved Motifs

• Author / Creator

  Mercier, Rebecca J

• Hsp90 is a highly conserved and essential molecular chaperone. It regulates the folding, maturation, and activation of client proteins involved in a wide range of cellular processes and pathways, many of which are key players in disease. Hsp90 functions in the context of an ATPase driven conformational cycle that is regulated by co-chaperone proteins. Aha-type co-chaperones are the most potent stimulators of the ATPase activity of Hsp90. Here we describe key structural elements required for the function of Aha-type co-chaperones and investigate the diverse roles of Aha-type co-chaperones in Hsp90 regulation. We show that the conserved N-terminal NxNNWHW motif is essential for the biological activity of Aha1p and Hch1p. This work points to a role for the NxNNWHW motif in regulating the apparent affinity of Hsp90 for nucleotide substrates and highlights the importance of nucleotide exchange in the Hsp90 functional cycle. In addition, we show that Lys 60 of the conserved RKxK motif is required for the in vivo and in vitro functions of Aha1p. While the in vivo requirements of Hch1p are consistent with Aha1p, all residues of the RKxK motif appear to be necessary for Hch1p-mediated stimulation of Hsp90. Our work in defining the conserved structural motifs in Aha-type co-chaperones, has provided insight into the ways in which the Aha-types co-chaperones regulate the conformational dynamics of Hsp90. We also investigated different models and approaches to understanding the regulation of Aha-type co-chaperones, which provides a valuable framework for future work to expand upon. Our broadened understanding of Aha-type co-chaperones, offers key insights into the mechanism of Hsp90 function and regulation.

• Subjects / Keywords

  • ATPase
  • Hch1
  • Hsp90
  • Aha1

• Graduation date

  Spring 2019

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/r3-tms0-be49

• License

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