UCSF

Small Heat Shock Proteins (sHSPs), including Hsp27, are a non-enzymatic

class of molecular chaperones that bind improperly folded proteins and maintain their

solubility, acting as a first line of defense against cellular stress. Through their ‘holdase’

function, the sHSPs are implicated in a variety of diseases that involve imbalances in

protein homeostasis, such as cancer and neurodegeneration. However, because they

form highly dynamic, polydisperse oligomers, it has been difficult to study how they work

and even what they interact with. This thesis explores the various protein-protein

interactions (PPIs) that involve the sHSPs (particularly Hsp27) as a way to clarify sHSP

function and guide future small-molecule development. Chapter one consists of a

review of the various PPIs within the chaperone network and highlights the critical role

of PPIs in facilitating cooperation between chaperone families, and how these individual

PPIs represent important targets for small-molecule discovery. Chapter two describes a

collaborative effort to characterize how point mutations within the Hsp70-sHSP adaptor

protein BAG3 can upend the function of the entire network and lead to disease.

Chapter three describes the characterization of Hsp27’s interaction with client protein

Tau and the important finding that client-binding sites are competitive with oligomeric

PPIs. Taken together, this work emphasizes the importance of individual interaction

interfaces in dictating function of a chaperone itself and in the context of the greater

network.