Heat shock protein 70 (Hsp70) is a molecular chaperone that regulates protein quality control. There are predicted Hsp70 binding sites in nearly 100% of protein-coding regions, although such regions are hydrophobic and expected to be inaccessible in the folded state. Thus, it remains unclear how many proteins actually bind Hsp70 in vivo. In this work, we have used newly identified Hsp70 inhibitors to probe the proteome-wide requirements for the first time. We found that Hsp70 inhibition caused degradation of several known chaperone substrates, including the microtubule-associated protein tau (MAPT). In addition, we have defined ~1000 proteins, including X-linked inhibitor of apoptosis protein (XIAP), that also appear to require Hsp70 for their stability. Biochemical studies have validated a subset of these interactions, suggesting that direct binding of Hsp70 to these proteins may protect them from degradation. Together, these studies help define the Hsp70-dependent proteome. Hsp70 has been linked to a number of protein misfolding disorders, so these results also provide a framework for understanding the roles of Hsp70 in pathophysiology.

Quantitative proteomics reveal a network of client proteins sensitive to Hsp70 inhibition

248th National Meeting (2014)

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