Quantitative Analysis of Hsp90-Client Interactions Reveals Principles of Substrate Recognition

By Mikko Taipale, Irina Krykbaeva, M. Koeva, C. Kayatekin, K. Westover, G. I. Karras, Susan Lindquist. Cell, 2012

859 citations recorded by the source corpus.

SUMMARY HSP90 is a molecular chaperone that associates with numerous substrate proteins called clients. It plays many important roles in human biology and medicine, but determinants of client recognition by HSP90 have remained frustratingly elusive. We systematically and quantitatively surveyed most human kinases, transcription factors, and E3 ligases for interaction with HSP90 and its cochaperone CDC37. Unexpectedly, many more kinases than transcription factors bound HSP90. CDC37 interacted with kinases, but not with transcription factors or E3 ligases. HSP90::kinase interactions varied continuously over a 100-fold range and provided a platform to study client protein recognition. In wild-type clients, HSP90 did not bind particular sequence motifs, but rather associated with intrinsically unstable kinases. Stabilization of the kinase in either its active or inactive conformation with diverse small molecules decreased HSP90 association. Our results establish HSP90 client recognition as a combinatorial process: CDC37 provides recognition of the kinase family, whereas thermodynamic parameters determine client binding within the family.

Subfields: Materials Chemistry, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/d102c643abfde56edaa203722bfd1b1b268f6af3

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In Materials Chemistry

1. M. Hayer-Hartl
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In Molecular Biology

1. F. Hartl
2. M. Hayer-Hartl
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Citations in the corpus

• Recent advances in the development of protein–protein interactions modulators: mechanisms and clinical trials (2020, background): “Among the numerous molecular chaperones of Hsp90, the value of cell division cycle protein 37 (Cdc37) has attracted much attention.(110) Many protein kinases (such as EGFR, CDK, Akt) rely on Cdc37 to aggregate onto Hsp90, thus completing the correct folding of the complex’s spatial conformation.”
• The heat‐shock protein/chaperone network and multiple stress resistance (2017, background): “Most human HSP90 clients are signalling components (Taipale et al., 2012) and it seems that similar principles apply to the plant kingdom (Iki et al.”
• In vivo aspects of protein folding and quality control (2016, background): “In eukaryotes Hsp90 supports not only protein folding, but also the conformational maturation and maintenance of a range of medically relevant signaling proteins, including proto-oncogenic kinases, steroid hormone receptors and transcription factors (106-110).”
• Pathways of cellular proteostasis in aging and disease (2018, background): “The highly conserved Hsp90 chaperone system also functions downstream of Hsp70 in maintaining a variety of signaling pathways via the folding and conformational regulation of their signal-transduction molecules (Sharma et al., 2012; Taipale et al., 2012).”
• Systematic Mutant Analyses Elucidate General and Client-Specific Aspects of Hsp90 Function. (2016, background): “Analyses of the affinities of kinases for Hsp90 inmammalian cells demonstrated that v-src had one of the strongest observed levels of associations with Hsp90 (Taipale et al., 2012).”