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Structural insights into the complex of oncogenic KRas4B G12V and Rgl2, a RalA/B activator.

التفاصيل البيبلوغرافية
العنوان: Structural insights into the complex of oncogenic KRas4B G12V and Rgl2, a RalA/B activator.
المؤلفون: Tariq M; https://ror.org/04h699437 Department of Molecular and Cell Biology, University of Leicester, Leicester, UK., Ikeya T; https://ror.org/00ws30h19 Department of Chemistry, Tokyo Metropolitan University, Hachioji, Japan., Togashi N; https://ror.org/00ws30h19 Department of Chemistry, Tokyo Metropolitan University, Hachioji, Japan., Fairall L; https://ror.org/04h699437 Department of Molecular and Cell Biology, University of Leicester, Leicester, UK.; https://ror.org/04h699437 Leicester Institute of Structure and Chemical Biology, University of Leicester, Leicester, UK., Kamei S; https://ror.org/00ws30h19 Department of Chemistry, Tokyo Metropolitan University, Hachioji, Japan., Mayooramurugan S; https://ror.org/04h699437 Department of Molecular and Cell Biology, University of Leicester, Leicester, UK., Abbott LR; https://ror.org/04h699437 Department of Molecular and Cell Biology, University of Leicester, Leicester, UK., Hasan A; https://ror.org/04h699437 Department of Molecular and Cell Biology, University of Leicester, Leicester, UK., Bueno-Alejo C; https://ror.org/04h699437 Leicester Institute of Structure and Chemical Biology, University of Leicester, Leicester, UK., Sukegawa S; https://ror.org/00ws30h19 Department of Chemistry, Tokyo Metropolitan University, Hachioji, Japan., Romartinez-Alonso B; https://ror.org/04h699437 Department of Molecular and Cell Biology, University of Leicester, Leicester, UK.; https://ror.org/04h699437 Leicester Institute of Structure and Chemical Biology, University of Leicester, Leicester, UK., Muro Campillo MA; https://ror.org/04h699437 Department of Molecular and Cell Biology, University of Leicester, Leicester, UK., Hudson AJ; https://ror.org/04h699437 Leicester Institute of Structure and Chemical Biology, University of Leicester, Leicester, UK.; https://ror.org/04h699437 Department of Chemistry, University of Leicester, Leicester, UK., Ito Y; https://ror.org/00ws30h19 Department of Chemistry, Tokyo Metropolitan University, Hachioji, Japan., Schwabe JW; https://ror.org/04h699437 Department of Molecular and Cell Biology, University of Leicester, Leicester, UK.; https://ror.org/04h699437 Leicester Institute of Structure and Chemical Biology, University of Leicester, Leicester, UK., Dominguez C; https://ror.org/04h699437 Department of Molecular and Cell Biology, University of Leicester, Leicester, UK.; https://ror.org/04h699437 Leicester Institute of Structure and Chemical Biology, University of Leicester, Leicester, UK., Tanaka K; https://ror.org/04h699437 Department of Molecular and Cell Biology, University of Leicester, Leicester, UK kt96@le.ac.uk.
المصدر: Life science alliance [Life Sci Alliance] 2023 Oct 13; Vol. 7 (1). Date of Electronic Publication: 2023 Oct 13 (Print Publication: 2024).
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Life Science Alliance, LLC Country of Publication: United States NLM ID: 101728869 Publication Model: Electronic-Print Cited Medium: Internet ISSN: 2575-1077 (Electronic) Linking ISSN: 25751077 NLM ISO Abbreviation: Life Sci Alliance Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [Woodbury, NY] : Life Science Alliance, LLC, [2018]-
مواضيع طبية MeSH: Monomeric GTP-Binding Proteins*/metabolism, Humans ; Signal Transduction/genetics ; Protein Isoforms/metabolism ; Genes, ras
مستخلص: About a quarter of total human cancers carry mutations in Ras isoforms. Accumulating evidence suggests that small GTPases, RalA, and RalB, and their activators, Ral guanine nucleotide exchange factors (RalGEFs), play an essential role in oncogenic Ras-induced signalling. We studied the interaction between human KRas4B and the Ras association (RA) domain of Rgl2 (Rgl2 RA ), one of the RA-containing RalGEFs. We show that the G12V oncogenic KRas4B mutation changes the interaction kinetics with Rgl2 RA The crystal structure of the KRas4B G12V : Rgl2 RA complex shows a 2:2 heterotetramer where the switch I and switch II regions of each KRas G12V interact with both Rgl2 RA molecules. This structural arrangement is highly similar to the HRas E31K :RALGDS RA crystal structure and is distinct from the well-characterised Ras:Raf complex. Interestingly, the G12V mutation was found at the dimer interface of KRas4B G12V with its partner. Our study reveals a potentially distinct mode of Ras:effector complex formation by RalGEFs and offers a possible mechanistic explanation for how the oncogenic KRas4B G12V hyperactivates the RalA/B pathway.
(© 2023 Tariq et al.)
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معلومات مُعتمدة: United Kingdom WT_ Wellcome Trust; 204801/Z/16/Z United Kingdom WT_ Wellcome Trust; BB/T00746X/1 United Kingdom BB_ Biotechnology and Biological Sciences Research Council
سلسلة جزيئية: PDB 1LFD; 1RLF; 6VJJ; 7SCW; 7SCX; 1HE8; 2C5L; 3DDC; 5P21; 8B69; 8AU4
المشرفين على المادة: EC 3.6.5.2 (Monomeric GTP-Binding Proteins)
0 (Protein Isoforms)
تواريخ الأحداث: Date Created: 20231013 Date Completed: 20231023 Latest Revision: 20240210
رمز التحديث: 20240210
مُعرف محوري في PubMed: PMC10576006
DOI: 10.26508/lsa.202302080
PMID: 37833074
قاعدة البيانات: MEDLINE
الوصف
تدمد:2575-1077
DOI:10.26508/lsa.202302080