Effector Binding Sequentially Alters KRAS Dimerization on the Membrane: New Insights Into RAS‐Mediated RAF Activation
Abstract: RAS proteins are peripheral membrane GTPases that activate multiple downstream effectors for cell proliferation and differentiation. The formation of a signaling RAS–RAF complex at the plasma membrane is implicated in a quarter of all human cancers; however, the underlying mechanism remains unclear. In this work, nanodisc platforms and paramagnetic relaxation enhancement (PRE) analyses to determine the structure of a hetero‐tetrameric complex comprising KRAS and the RAS‐binding domain (RBD) and cysteine‐rich domain (CRD) of activated RAF1 are employed. The binding of the RBD or RBD–CRD differentially alters the dimerization modes of KRAS on both anionic and neutral membranes, validated by interface‐specific mutagenesis. Notably, the RBD binding allosterically generated two distinct KRAS dimer interfaces in equilibrium, favored by KRAS free and in complex with the RBD–CRD, respectively. Additional interactions of the CRD with both KRAS protomers are mutually cooperative to stabilize a new dimer configuration of KRAS bound to the RBD–CRD. The RAF binding sequentially alters KRAS dimerization, providing new insights into RAF activation, including a configurational transition of the KRAS dimer to provide an interaction site for the CRD and release the autoinhibited RAF complex. These methods are applicable to many other signaling protein complexes on the membrane.
- Location
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Deutsche Nationalbibliothek Frankfurt am Main
- Extent
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Online-Ressource
- Language
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Englisch
- Bibliographic citation
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Effector Binding Sequentially Alters KRAS Dimerization on the Membrane: New Insights Into RAS‐Mediated RAF Activation ; day:13 ; month:08 ; year:2024 ; extent:13
Advanced science ; (13.08.2024) (gesamt 13)
- Creator
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Lee, Soo‐Yeon
Eun, Hyun‐Jong
Lee, Ki‐Young
- DOI
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10.1002/advs.202401530
- URN
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urn:nbn:de:101:1-2408141430144.486371300664
- Rights
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Last update
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14.08.2025, 10:54 AM CEST
Data provider
Deutsche Nationalbibliothek. If you have any questions about the object, please contact the data provider.
Associated
- Lee, Soo‐Yeon
- Eun, Hyun‐Jong
- Lee, Ki‐Young
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