Tumor-derived RHOA mutants interact with effectors in the GDP-bound state.

Autor: Lin Y; Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. yuan.lin@cchmc.org., Ramelot TA; Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, USA., Senyuz S; Computational Sciences and Engineering, Koc University, Rumelifeneri Yolu, Istanbul, Turkey., Gursoy A; Department of Computer Engineering, Koc Univeristy, Rumelifeneri Yolu, Istanbul, Turkey., Jang H; Computational Structural Biology Section, Frederick National Laboratory for Cancer Research in the Cancer Innovation Laboratory, National Cancer Institute, Frederick, MD, USA., Nussinov R; Computational Structural Biology Section, Frederick National Laboratory for Cancer Research in the Cancer Innovation Laboratory, National Cancer Institute, Frederick, MD, USA., Keskin O; Department of Chemical and Biological Engineering, Koc Univeristy, Rumelifeneri Yolu, Istanbul, Turkey., Zheng Y; Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. yi.zheng@cchmc.org.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Aug 21; Vol. 15 (1), pp. 7176. Date of Electronic Publication: 2024 Aug 21.
DOI: 10.1038/s41467-024-51445-z
Abstrakt: RHOA mutations are found at diverse residues in various cancer types, implying mutation- and cell-specific mechanisms of tumorigenesis. Here, we focus on the underlying mechanisms of two gain-of-function RHOA mutations, A161P and A161V, identified in adult T-cell leukemia/lymphoma. We find that RHOA A161P and RHOA A161V are both fast-cycling mutants with increased guanine nucleotide dissociation/association rates compared with RHOA WT and show reduced GTP-hydrolysis activity. Crystal structures reveal an altered nucleotide association in RHOA A161P and an open nucleotide pocket in RHOA A161V . Both mutations perturb the dynamic properties of RHOA switch regions and shift the conformational landscape important for RHOA activity, as shown by 31 P NMR and molecular dynamics simulations. Interestingly, RHOA A161P and RHOA A161V can interact with effectors in the GDP-bound state. 1 H- 15 N HSQC NMR spectra support the existence of an active population in RHOA A161V -GDP. The distinct interaction mechanisms resulting from the mutations likely favor an RHOA WT -like "ON" conformation, endowing GDP-bound state effector binding activity.
(© 2024. The Author(s).)
Databáze: MEDLINE
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