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Conserved allosteric perturbation of the GTPase domains by region 1 of Ras hypervariable regions.
Gu, Xue; Zhang, Yalong; Long, Dong.
Afiliación
  • Gu X; MOE Key Laboratory for Cellular Dynamics, School of Life Sciences, University of Science and Technology of China, Hefei, China.
  • Zhang Y; MOE Key Laboratory for Cellular Dynamics, School of Life Sciences, University of Science and Technology of China, Hefei, China.
  • Long D; MOE Key Laboratory for Cellular Dynamics, School of Life Sciences, University of Science and Technology of China, Hefei, China; Department of Chemistry, University of Science and Technology of China, Hefei, China. Electronic address: dlong@ustc.edu.cn.
Biophys J ; 123(7): 839-846, 2024 Apr 02.
Article en En | MEDLINE | ID: mdl-38419331
ABSTRACT
Ras proteins are important intracellular signaling hubs that can interact with numerous downstream effectors and upstream regulators through their GTPase domains (G-domains) anchored to plasma membranes by the C-terminal hypervariable regions (HVRs). The biological functions of Ras were proposed to be regulated at multiple levels including the intramolecular G-domain-HVR interactions, of which the exact mechanism and specificity are still controversial. Here, we demonstrate that the HVRs, instead of having direct contacts, can weakly perturb the G-domains via an allosteric interaction that is restricted to a ∼20 Å range and highly conserved in the tested Ras isoforms (HRas and KRas4B) and nucleotide-bound states. The origin of this allosteric perturbation has been localized to a short segment (residues 167-171) coinciding with region 1 of HVRs, which exhibits moderate to weak α-helical propensities. A charge-reversal mutation (E168K) of KRas4B in region 1, previously described in the Catalog of Somatic Mutations in Cancer database, was found to induce similar chemical shift perturbations as truncation of the HVR does. Further membrane paramagnetic relaxation enhancement (mPRE) data show that this region 1 mutation alters the membrane orientations of KRas4B and moderately increases the relative population of the signaling-compatible state.
Asunto(s)

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Transducción de Señal / Proteínas ras Idioma: En Revista: Biophys J Año: 2024 Tipo del documento: Article País de afiliación: China

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Transducción de Señal / Proteínas ras Idioma: En Revista: Biophys J Año: 2024 Tipo del documento: Article País de afiliación: China