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

Yuan Lin (), Theresa A. Ramelot, Simge Senyuz, Attila Gursoy, Hyunbum Jang, Ruth Nussinov, Ozlem Keskin and Yi Zheng ()
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Yuan Lin: Cincinnati Children’s Hospital Medical Center
Theresa A. Ramelot: Rensselaer Polytechnic Institute
Simge Senyuz: Rumelifeneri Yolu
Attila Gursoy: Rumelifeneri Yolu
Hyunbum Jang: National Cancer Institute
Ruth Nussinov: National Cancer Institute
Ozlem Keskin: Rumelifeneri Yolu
Yi Zheng: Cincinnati Children’s Hospital Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract 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 RHOAA161P and RHOAA161V are both fast-cycling mutants with increased guanine nucleotide dissociation/association rates compared with RHOAWT and show reduced GTP-hydrolysis activity. Crystal structures reveal an altered nucleotide association in RHOAA161P and an open nucleotide pocket in RHOAA161V. Both mutations perturb the dynamic properties of RHOA switch regions and shift the conformational landscape important for RHOA activity, as shown by 31P NMR and molecular dynamics simulations. Interestingly, RHOAA161P and RHOAA161V can interact with effectors in the GDP-bound state. 1H-15N HSQC NMR spectra support the existence of an active population in RHOAA161V-GDP. The distinct interaction mechanisms resulting from the mutations likely favor an RHOAWT-like “ON” conformation, endowing GDP-bound state effector binding activity.

Date: 2024
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DOI: 10.1038/s41467-024-51445-z

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