Quantitative Analysis of Hsp90-Client Interactions Reveals Principles of Substrate Recognition
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 k...
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| Format: | Article |
| Language: | en_US |
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Elsevier
2014
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| Online Access: | http://hdl.handle.net/1721.1/91538 https://orcid.org/0000-0003-1307-882X https://orcid.org/0000-0001-7024-0921 |
| _version_ | 1811070389002960896 |
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| author | Taipale, Mikko Krykbaeva, Irina Kayatekin, Can Westover, Kenneth D. Karras, Georgios I. Lindquist, Susan Koeva, Martina I |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Taipale, Mikko Krykbaeva, Irina Kayatekin, Can Westover, Kenneth D. Karras, Georgios I. Lindquist, Susan Koeva, Martina I |
| author_sort | Taipale, Mikko |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T08:35:11Z |
| format | Article |
| id | mit-1721.1/91538 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T08:35:11Z |
| publishDate | 2014 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/915382022-09-23T13:05:42Z Quantitative Analysis of Hsp90-Client Interactions Reveals Principles of Substrate Recognition Taipale, Mikko Krykbaeva, Irina Kayatekin, Can Westover, Kenneth D. Karras, Georgios I. Lindquist, Susan Koeva, Martina I Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Biology Whitehead Institute for Biomedical Research Koeva, Martina I. Lindquist, Susan 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. National Institutes of Health (U.S.). Genomics Based Drug Discovery-Driving Medical Project (Grant UL1-DE019585) National Institutes of Health (U.S.) (Grant RL1-GM084437) National Institutes of Health (U.S.) (Grant RL1-CA133834) National Institutes of Health (U.S.) (Grant RL1-HG004671) 2014-11-13T18:00:01Z 2014-11-13T18:00:01Z 2012-08 2012-05 Article http://purl.org/eprint/type/JournalArticle 00928674 1097-4172 http://hdl.handle.net/1721.1/91538 Taipale, Mikko, Irina Krykbaeva, Martina Koeva, Can Kayatekin, Kenneth D. Westover, Georgios I. Karras, and Susan Lindquist. “Quantitative Analysis of Hsp90-Client Interactions Reveals Principles of Substrate Recognition.” Cell 150, no. 5 (August 2012): 987–1001. © 2012 Elsevier Inc. https://orcid.org/0000-0003-1307-882X https://orcid.org/0000-0001-7024-0921 en_US http://dx.doi.org/10.1016/j.cell.2012.06.047 Cell Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Elsevier Elsevier |
| spellingShingle | Taipale, Mikko Krykbaeva, Irina Kayatekin, Can Westover, Kenneth D. Karras, Georgios I. Lindquist, Susan Koeva, Martina I Quantitative Analysis of Hsp90-Client Interactions Reveals Principles of Substrate Recognition |
| title | Quantitative Analysis of Hsp90-Client Interactions Reveals Principles of Substrate Recognition |
| title_full | Quantitative Analysis of Hsp90-Client Interactions Reveals Principles of Substrate Recognition |
| title_fullStr | Quantitative Analysis of Hsp90-Client Interactions Reveals Principles of Substrate Recognition |
| title_full_unstemmed | Quantitative Analysis of Hsp90-Client Interactions Reveals Principles of Substrate Recognition |
| title_short | Quantitative Analysis of Hsp90-Client Interactions Reveals Principles of Substrate Recognition |
| title_sort | quantitative analysis of hsp90 client interactions reveals principles of substrate recognition |
| url | http://hdl.handle.net/1721.1/91538 https://orcid.org/0000-0003-1307-882X https://orcid.org/0000-0001-7024-0921 |
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