Heterogeneous binding of the SH3 client protein to the DnaK molecular chaperone
The molecular chaperone heat shock protein 70 (Hsp70) plays a vital role in cellular processes, including protein folding and assembly, and helps prevent aggregation under physiological and stress-related conditions. Although the structural changes undergone by full-length client proteins upon inter...
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Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2015-08, Vol.112 (31), p.E4206-E4215 |
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description | The molecular chaperone heat shock protein 70 (Hsp70) plays a vital role in cellular processes, including protein folding and assembly, and helps prevent aggregation under physiological and stress-related conditions. Although the structural changes undergone by full-length client proteins upon interaction with DnaK (i.e.,Escherichia coliHsp70) are fundamental to understand chaperone-mediated protein folding, these changes are still largely unexplored. Here, we show that multiple conformations of the SRC homology 3 domain (SH3) client protein interact with the ADP-bound form of the DnaK chaperone. Chaperone-bound SH3 is largely unstructured yet distinct from the unfolded state in the absence of DnaK. The bound client protein shares a highly flexible N terminus and multiple slowly interconverting conformations in different parts of the sequence. In all, there is significant structural and dynamical heterogeneity in the DnaK-bound client protein, revealing that proteins may undergo some conformational sampling while chaperone-bound. This result is important because it shows that the surface of the Hsp70 chaperone provides an aggregation-free environment able to support part of the search for the native state. |
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Although the structural changes undergone by full-length client proteins upon interaction with DnaK (i.e.,Escherichia coliHsp70) are fundamental to understand chaperone-mediated protein folding, these changes are still largely unexplored. Here, we show that multiple conformations of the SRC homology 3 domain (SH3) client protein interact with the ADP-bound form of the DnaK chaperone. Chaperone-bound SH3 is largely unstructured yet distinct from the unfolded state in the absence of DnaK. The bound client protein shares a highly flexible N terminus and multiple slowly interconverting conformations in different parts of the sequence. In all, there is significant structural and dynamical heterogeneity in the DnaK-bound client protein, revealing that proteins may undergo some conformational sampling while chaperone-bound. This result is important because it shows that the surface of the Hsp70 chaperone provides an aggregation-free environment able to support part of the search for the native state.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1505173112</identifier><identifier>PMID: 26195753</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Adenosine Diphosphate - metabolism ; Animals ; Biological Sciences ; Drosophila melanogaster ; Drosophila Proteins - chemistry ; Drosophila Proteins - metabolism ; E coli ; Escherichia coli ; Escherichia coli Proteins - chemistry ; Escherichia coli Proteins - metabolism ; Heat shock proteins ; HSP70 Heat-Shock Proteins - chemistry ; HSP70 Heat-Shock Proteins - metabolism ; Magnetic Resonance Spectroscopy ; Models, Biological ; Molecular Chaperones - chemistry ; Molecular Chaperones - metabolism ; Molecules ; PNAS Plus ; Protein Binding ; Protein Conformation ; Protein Folding ; Solvents ; src Homology Domains ; Substrate Specificity</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2015-08, Vol.112 (31), p.E4206-E4215</ispartof><rights>Volumes 1–89 and 106–112, copyright as a collective work only; author(s) retains copyright to individual articles</rights><rights>Copyright National Academy of Sciences Aug 4, 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c501t-7d60b6190d7966f9170f4f33838db03a68b2f4e5185d19c0a52b879303e0f8e53</citedby><cites>FETCH-LOGICAL-c501t-7d60b6190d7966f9170f4f33838db03a68b2f4e5185d19c0a52b879303e0f8e53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/112/31.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/26464311$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/26464311$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,803,885,27924,27925,53791,53793,58017,58250</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26195753$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lee, Jung Ho</creatorcontrib><creatorcontrib>Zhang, Dongyu</creatorcontrib><creatorcontrib>Hughes, Christopher</creatorcontrib><creatorcontrib>Okuno, Yusuke</creatorcontrib><creatorcontrib>Sekhar, Ashok</creatorcontrib><creatorcontrib>Cavagnero, Silvia</creatorcontrib><title>Heterogeneous binding of the SH3 client protein to the DnaK molecular chaperone</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>The molecular chaperone heat shock protein 70 (Hsp70) plays a vital role in cellular processes, including protein folding and assembly, and helps prevent aggregation under physiological and stress-related conditions. 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This result is important because it shows that the surface of the Hsp70 chaperone provides an aggregation-free environment able to support part of the search for the native state.</description><subject>Adenosine Diphosphate - metabolism</subject><subject>Animals</subject><subject>Biological Sciences</subject><subject>Drosophila melanogaster</subject><subject>Drosophila Proteins - chemistry</subject><subject>Drosophila Proteins - metabolism</subject><subject>E coli</subject><subject>Escherichia coli</subject><subject>Escherichia coli Proteins - chemistry</subject><subject>Escherichia coli Proteins - metabolism</subject><subject>Heat shock proteins</subject><subject>HSP70 Heat-Shock Proteins - chemistry</subject><subject>HSP70 Heat-Shock Proteins - metabolism</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Models, Biological</subject><subject>Molecular Chaperones - chemistry</subject><subject>Molecular Chaperones - metabolism</subject><subject>Molecules</subject><subject>PNAS Plus</subject><subject>Protein Binding</subject><subject>Protein Conformation</subject><subject>Protein Folding</subject><subject>Solvents</subject><subject>src Homology Domains</subject><subject>Substrate Specificity</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkTtvFDEUhS0EIkugpgJZokkzyfXbbpCiJLCISCmA2vLMeHZnNWsP9gwS_x7vgyVQUbm43z0-9xyEXhO4JKDY1RhcviQCBFGMEPoELQgYUklu4ClaAFBVaU75GXqR8wYAjNDwHJ1RSYxQgi3Qw9JPPsWVDz7OGdd9aPuwwrHD09rjL0uGm6H3YcJjipPvA57ifnIb3Ge8jYNv5sEl3KzdWGSCf4medW7I_tXxPUffPtx9vVlW9w8fP91c31eNADJVqpVQFxPQKiNlZ4iCjneMaabbGpiTuqYd94Jo0RLTgBO01sowYB467QU7R-8PuuNcb33bFIvJDXZM_dalnza63v49Cf3aruIPywUrgfAicHEUSPH77PNkt31u_DC4fRKWKKJKilrp_0CBgqFUQkHf_YNu4pxCSWJPaSVA78xfHagmxZyT706-Cdhdr3bXq_3Ta9l4-_jcE_-7yALgI7DbPMkRahmxd5yCLMibA7LJU0yPJLjk5RP2Cx8rsNs</recordid><startdate>20150804</startdate><enddate>20150804</enddate><creator>Lee, Jung Ho</creator><creator>Zhang, Dongyu</creator><creator>Hughes, Christopher</creator><creator>Okuno, Yusuke</creator><creator>Sekhar, Ashok</creator><creator>Cavagnero, Silvia</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>7ST</scope><scope>SOI</scope><scope>5PM</scope></search><sort><creationdate>20150804</creationdate><title>Heterogeneous binding of the SH3 client protein to the DnaK molecular chaperone</title><author>Lee, Jung Ho ; Zhang, Dongyu ; Hughes, Christopher ; Okuno, Yusuke ; Sekhar, Ashok ; Cavagnero, Silvia</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c501t-7d60b6190d7966f9170f4f33838db03a68b2f4e5185d19c0a52b879303e0f8e53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Adenosine Diphosphate - metabolism</topic><topic>Animals</topic><topic>Biological Sciences</topic><topic>Drosophila melanogaster</topic><topic>Drosophila Proteins - chemistry</topic><topic>Drosophila Proteins - metabolism</topic><topic>E coli</topic><topic>Escherichia coli</topic><topic>Escherichia coli Proteins - chemistry</topic><topic>Escherichia coli Proteins - metabolism</topic><topic>Heat shock proteins</topic><topic>HSP70 Heat-Shock Proteins - chemistry</topic><topic>HSP70 Heat-Shock Proteins - metabolism</topic><topic>Magnetic Resonance Spectroscopy</topic><topic>Models, Biological</topic><topic>Molecular Chaperones - chemistry</topic><topic>Molecular Chaperones - metabolism</topic><topic>Molecules</topic><topic>PNAS Plus</topic><topic>Protein Binding</topic><topic>Protein Conformation</topic><topic>Protein Folding</topic><topic>Solvents</topic><topic>src Homology Domains</topic><topic>Substrate Specificity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lee, Jung Ho</creatorcontrib><creatorcontrib>Zhang, Dongyu</creatorcontrib><creatorcontrib>Hughes, Christopher</creatorcontrib><creatorcontrib>Okuno, Yusuke</creatorcontrib><creatorcontrib>Sekhar, Ashok</creatorcontrib><creatorcontrib>Cavagnero, Silvia</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>Environment Abstracts</collection><collection>Environment Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lee, Jung Ho</au><au>Zhang, Dongyu</au><au>Hughes, Christopher</au><au>Okuno, Yusuke</au><au>Sekhar, Ashok</au><au>Cavagnero, Silvia</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Heterogeneous binding of the SH3 client protein to the DnaK molecular chaperone</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2015-08-04</date><risdate>2015</risdate><volume>112</volume><issue>31</issue><spage>E4206</spage><epage>E4215</epage><pages>E4206-E4215</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>The molecular chaperone heat shock protein 70 (Hsp70) plays a vital role in cellular processes, including protein folding and assembly, and helps prevent aggregation under physiological and stress-related conditions. Although the structural changes undergone by full-length client proteins upon interaction with DnaK (i.e.,Escherichia coliHsp70) are fundamental to understand chaperone-mediated protein folding, these changes are still largely unexplored. Here, we show that multiple conformations of the SRC homology 3 domain (SH3) client protein interact with the ADP-bound form of the DnaK chaperone. Chaperone-bound SH3 is largely unstructured yet distinct from the unfolded state in the absence of DnaK. The bound client protein shares a highly flexible N terminus and multiple slowly interconverting conformations in different parts of the sequence. In all, there is significant structural and dynamical heterogeneity in the DnaK-bound client protein, revealing that proteins may undergo some conformational sampling while chaperone-bound. 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subjects | Adenosine Diphosphate - metabolism Animals Biological Sciences Drosophila melanogaster Drosophila Proteins - chemistry Drosophila Proteins - metabolism E coli Escherichia coli Escherichia coli Proteins - chemistry Escherichia coli Proteins - metabolism Heat shock proteins HSP70 Heat-Shock Proteins - chemistry HSP70 Heat-Shock Proteins - metabolism Magnetic Resonance Spectroscopy Models, Biological Molecular Chaperones - chemistry Molecular Chaperones - metabolism Molecules PNAS Plus Protein Binding Protein Conformation Protein Folding Solvents src Homology Domains Substrate Specificity |
title | Heterogeneous binding of the SH3 client protein to the DnaK molecular chaperone |
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