Small GTPase Ran: Depicting the nucleotide-specific conformational landscape of the functionally important C-terminus.

Autor:	Czigleczki J; Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary., de Resende Lara PT; Department of Medical Genetics and Genomic Medicine, School of Medical Sciences, University of Campinas-UNICAMP, Campinas, Brazil., Dudas B; Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary.; Inserm U1268 MCTR, CiTCoM UMR 8038 CNRS-Université Paris Cité, Paris, France.; Laboratoire et Biologie et Pharmacologie Appliquée, Ecole Normale Supérieure Paris-Saclay, Gif-sur-Yvette, France., Jang H; Computational Structural Biology Section, Frederick National Laboratory for Cancer Research in the Cancer Innovation Laboratory, National Cancer Institute, Frederick, MD, United States., Perahia D; Laboratoire et Biologie et Pharmacologie Appliquée, Ecole Normale Supérieure Paris-Saclay, Gif-sur-Yvette, France., Nussinov R; Computational Structural Biology Section, Frederick National Laboratory for Cancer Research in the Cancer Innovation Laboratory, National Cancer Institute, Frederick, MD, United States.; Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel., Balog E; Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary.
Jazyk:	angličtina
Zdroj:	Frontiers in molecular biosciences [Front Mol Biosci] 2023 Jan 16; Vol. 10, pp. 1111574. Date of Electronic Publication: 2023 Jan 16 (Print Publication: 2023).
DOI:	10.3389/fmolb.2023.1111574
Abstrakt:	The small GTPase Ran is the main regulator of the nucleo-cytoplasmic import and export through the nuclear pore complex. It functions as a molecular switch cycling between the GDP-bound inactive and GTP-bound active state. It consists of a globular (G) domain and a C-terminal region, which is bound to the G-domain in the inactive, GDP-bound states. Crystal structures of the GTP-bound active form complexed with Ran binding proteins (RanBP) show that the C-terminus undergoes a large conformational change, embracing Ran binding domains (RanBD). Whereas in the crystal structures of macromolecular complexes not containing RanBDs the structure of the C-terminal segment remains unresolved, indicating its large conformational flexibility. This movement could not have been followed either by experimental or simulation methods. Here, starting from the crystal structure of Ran in both GDP- and GTP-bound forms we show how rigid the C-terminal region in the inactive structure is during molecular dynamics (MD) simulations. Furthermore, we show how MD simulations of the active form are incapable of mapping the open conformations of the C-terminus. By using the MDeNM (Molecular Dynamics with excited Normal Modes) method, we were able to widely map the conformational surface of the C-terminus of Ran in the active GTP-bound form, which allows us to envisage how it can embrace RanBDs. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2023 Czigleczki, de Resende Lara, Dudas, Jang, Perahia, Nussinov and Balog.)
Databáze:	MEDLINE
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