Raf promotes dimerization of the Ras G-domain with increased allosteric connections
Ras dimerization is critical for Raf activation. Here we show that the Ras binding domain of Raf (Raf-RBD) induces robust Ras dimerization at low surface densities on supported lipid bilayers and, to a lesser extent, in solution as observed by size exclusion chromatography and confirmed by SAXS. Com...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2021-03, Vol.118 (10), p.1-11 |
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| creator | Packer, Morgan R. Parker, Jillian A. Chung, Jean K. Li, Zhenlu Lee, Young Kwang Cookis, Trinity Guterres, Hugo Alvarez, Steven Hossain, Md Amin Donnelly, Daniel P. Agar, Jeffrey N. Makowski, Lee Buck, Matthias Groves, Jay T. Mattos, Carla |
| description | Ras dimerization is critical for Raf activation. Here we show that the Ras binding domain of Raf (Raf-RBD) induces robust Ras dimerization at low surface densities on supported lipid bilayers and, to a lesser extent, in solution as observed by size exclusion chromatography and confirmed by SAXS. Community network analysis based on molecular dynamics simulations shows robust allosteric connections linking the two Raf-RBD D113 residues located in the Galectin scaffold protein binding site of each Raf-RBD molecule and 85 Å apart on opposite ends of the dimer complex. Our results suggest that Raf-RBD binding and Ras dimerization are concerted events that lead to a high-affinity signaling complex at the membrane that we propose is an essential unit in the macromolecular assembly of higher order Ras/Raf/Galectin complexes important for signaling through the Ras/Raf/MEK/ERK pathway. |
| doi_str_mv | 10.1073/pnas.2015648118 |
| format | Article |
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Here we show that the Ras binding domain of Raf (Raf-RBD) induces robust Ras dimerization at low surface densities on supported lipid bilayers and, to a lesser extent, in solution as observed by size exclusion chromatography and confirmed by SAXS. Community network analysis based on molecular dynamics simulations shows robust allosteric connections linking the two Raf-RBD D113 residues located in the Galectin scaffold protein binding site of each Raf-RBD molecule and 85 Å apart on opposite ends of the dimer complex. Our results suggest that Raf-RBD binding and Ras dimerization are concerted events that lead to a high-affinity signaling complex at the membrane that we propose is an essential unit in the macromolecular assembly of higher order Ras/Raf/Galectin complexes important for signaling through the Ras/Raf/MEK/ERK pathway.</description><identifier>ISSN: 0027-8424</identifier><identifier>ISSN: 1091-6490</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.2015648118</identifier><identifier>PMID: 33653954</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Allosteric properties ; Binding sites ; Biological Sciences ; Dimerization ; Dimers ; Domains ; Galectins - chemistry ; Galectins - genetics ; Galectins - metabolism ; Humans ; Lipid bilayers ; Lipids ; Macromolecules ; Metabolic pathways ; Molecular dynamics ; Molecular Dynamics Simulation ; Network analysis ; Protein Domains ; Proto-Oncogene Proteins p21(ras) - chemistry ; Proto-Oncogene Proteins p21(ras) - genetics ; Proto-Oncogene Proteins p21(ras) - metabolism ; raf Kinases - chemistry ; raf Kinases - genetics ; raf Kinases - metabolism ; Raf protein ; Ras protein ; Robustness ; Signaling ; Size exclusion chromatography</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2021-03, Vol.118 (10), p.1-11</ispartof><rights>Copyright National Academy of Sciences Mar 9, 2021</rights><rights>2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c443t-1524710001971c6442db377833b67ca1c7182f448fb83b55fd3d3e119578730c3</citedby><cites>FETCH-LOGICAL-c443t-1524710001971c6442db377833b67ca1c7182f448fb83b55fd3d3e119578730c3</cites><orcidid>0000-0003-2645-1873 ; 0000-0003-2101-8237 ; 0000-0001-7136-503X ; 0000-0002-5145-7508 ; 0000-0001-7683-8385 ; 0000-0003-1090-943X ; 0000-0002-2958-0403 ; 0000-0002-4112-0696 ; 0000-0003-0056-6357</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/27027500$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/27027500$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,803,885,27915,27916,53782,53784,58008,58241</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33653954$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Packer, Morgan R.</creatorcontrib><creatorcontrib>Parker, Jillian A.</creatorcontrib><creatorcontrib>Chung, Jean K.</creatorcontrib><creatorcontrib>Li, Zhenlu</creatorcontrib><creatorcontrib>Lee, Young Kwang</creatorcontrib><creatorcontrib>Cookis, Trinity</creatorcontrib><creatorcontrib>Guterres, Hugo</creatorcontrib><creatorcontrib>Alvarez, Steven</creatorcontrib><creatorcontrib>Hossain, Md Amin</creatorcontrib><creatorcontrib>Donnelly, Daniel P.</creatorcontrib><creatorcontrib>Agar, Jeffrey N.</creatorcontrib><creatorcontrib>Makowski, Lee</creatorcontrib><creatorcontrib>Buck, Matthias</creatorcontrib><creatorcontrib>Groves, Jay T.</creatorcontrib><creatorcontrib>Mattos, Carla</creatorcontrib><title>Raf promotes dimerization of the Ras G-domain with increased allosteric connections</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Ras dimerization is critical for Raf activation. Here we show that the Ras binding domain of Raf (Raf-RBD) induces robust Ras dimerization at low surface densities on supported lipid bilayers and, to a lesser extent, in solution as observed by size exclusion chromatography and confirmed by SAXS. Community network analysis based on molecular dynamics simulations shows robust allosteric connections linking the two Raf-RBD D113 residues located in the Galectin scaffold protein binding site of each Raf-RBD molecule and 85 Å apart on opposite ends of the dimer complex. Our results suggest that Raf-RBD binding and Ras dimerization are concerted events that lead to a high-affinity signaling complex at the membrane that we propose is an essential unit in the macromolecular assembly of higher order Ras/Raf/Galectin complexes important for signaling through the Ras/Raf/MEK/ERK pathway.</description><subject>Allosteric properties</subject><subject>Binding sites</subject><subject>Biological Sciences</subject><subject>Dimerization</subject><subject>Dimers</subject><subject>Domains</subject><subject>Galectins - chemistry</subject><subject>Galectins - genetics</subject><subject>Galectins - metabolism</subject><subject>Humans</subject><subject>Lipid bilayers</subject><subject>Lipids</subject><subject>Macromolecules</subject><subject>Metabolic pathways</subject><subject>Molecular dynamics</subject><subject>Molecular Dynamics Simulation</subject><subject>Network analysis</subject><subject>Protein Domains</subject><subject>Proto-Oncogene Proteins p21(ras) - chemistry</subject><subject>Proto-Oncogene Proteins p21(ras) - genetics</subject><subject>Proto-Oncogene Proteins p21(ras) - metabolism</subject><subject>raf Kinases - chemistry</subject><subject>raf Kinases - genetics</subject><subject>raf Kinases - metabolism</subject><subject>Raf protein</subject><subject>Ras protein</subject><subject>Robustness</subject><subject>Signaling</subject><subject>Size exclusion chromatography</subject><issn>0027-8424</issn><issn>1091-6490</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc9rFDEUx0NR2nX13JMS8NLLtHn5MclcBCn9IRSEqueQyWTcLDPJmmSV9q83y9atCoEc3uf7eO99EDoFcg5EsotNMPmcEhAtVwDqCC2AdNC0vCMv0IIQKhvFKT9Br3JeE0I6ocgxOmGsFawTfIG-3JsRb1KcY3EZD352yT-a4mPAccRl5fC9yfimGeJsfMC_fFlhH2xyJrsBm2mKudSIxTaG4OwumF-jl6OZsnvz9C_Rt-urr5e3zd3nm0-XH-8ayzkrDQjKJdShoJNgW87p0DMpFWN9K60BK0HRkXM19or1QowDG5gD6IRUkhHLlujDvu9m289usC6UZCa9SX426UFH4_W_leBX-nv8qWU9A6tvic6eGqT4Y-ty0bPP1k2TCS5us6a8aymTRLYVff8fuo7bFOp6O0pxDkBopS72lE0x5-TGwzBA9E6Y3gnTz8Jq4t3fOxz4P4Yq8HYPrHOJ6VCnsroVhLDfv1yaxQ</recordid><startdate>20210309</startdate><enddate>20210309</enddate><creator>Packer, Morgan R.</creator><creator>Parker, Jillian A.</creator><creator>Chung, Jean K.</creator><creator>Li, Zhenlu</creator><creator>Lee, Young Kwang</creator><creator>Cookis, Trinity</creator><creator>Guterres, Hugo</creator><creator>Alvarez, Steven</creator><creator>Hossain, Md Amin</creator><creator>Donnelly, Daniel P.</creator><creator>Agar, Jeffrey N.</creator><creator>Makowski, Lee</creator><creator>Buck, Matthias</creator><creator>Groves, Jay T.</creator><creator>Mattos, Carla</creator><general>National Academy of 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>5PM</scope><orcidid>https://orcid.org/0000-0003-2645-1873</orcidid><orcidid>https://orcid.org/0000-0003-2101-8237</orcidid><orcidid>https://orcid.org/0000-0001-7136-503X</orcidid><orcidid>https://orcid.org/0000-0002-5145-7508</orcidid><orcidid>https://orcid.org/0000-0001-7683-8385</orcidid><orcidid>https://orcid.org/0000-0003-1090-943X</orcidid><orcidid>https://orcid.org/0000-0002-2958-0403</orcidid><orcidid>https://orcid.org/0000-0002-4112-0696</orcidid><orcidid>https://orcid.org/0000-0003-0056-6357</orcidid></search><sort><creationdate>20210309</creationdate><title>Raf promotes dimerization of the Ras G-domain with increased allosteric connections</title><author>Packer, Morgan R. ; 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Here we show that the Ras binding domain of Raf (Raf-RBD) induces robust Ras dimerization at low surface densities on supported lipid bilayers and, to a lesser extent, in solution as observed by size exclusion chromatography and confirmed by SAXS. Community network analysis based on molecular dynamics simulations shows robust allosteric connections linking the two Raf-RBD D113 residues located in the Galectin scaffold protein binding site of each Raf-RBD molecule and 85 Å apart on opposite ends of the dimer complex. Our results suggest that Raf-RBD binding and Ras dimerization are concerted events that lead to a high-affinity signaling complex at the membrane that we propose is an essential unit in the macromolecular assembly of higher order Ras/Raf/Galectin complexes important for signaling through the Ras/Raf/MEK/ERK pathway.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>33653954</pmid><doi>10.1073/pnas.2015648118</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0003-2645-1873</orcidid><orcidid>https://orcid.org/0000-0003-2101-8237</orcidid><orcidid>https://orcid.org/0000-0001-7136-503X</orcidid><orcidid>https://orcid.org/0000-0002-5145-7508</orcidid><orcidid>https://orcid.org/0000-0001-7683-8385</orcidid><orcidid>https://orcid.org/0000-0003-1090-943X</orcidid><orcidid>https://orcid.org/0000-0002-2958-0403</orcidid><orcidid>https://orcid.org/0000-0002-4112-0696</orcidid><orcidid>https://orcid.org/0000-0003-0056-6357</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Allosteric properties Binding sites Biological Sciences Dimerization Dimers Domains Galectins - chemistry Galectins - genetics Galectins - metabolism Humans Lipid bilayers Lipids Macromolecules Metabolic pathways Molecular dynamics Molecular Dynamics Simulation Network analysis Protein Domains Proto-Oncogene Proteins p21(ras) - chemistry Proto-Oncogene Proteins p21(ras) - genetics Proto-Oncogene Proteins p21(ras) - metabolism raf Kinases - chemistry raf Kinases - genetics raf Kinases - metabolism Raf protein Ras protein Robustness Signaling Size exclusion chromatography |
| title | Raf promotes dimerization of the Ras G-domain with increased allosteric connections |
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