TY - JOUR
T1 - Small GTPase Ran
T2 - Depicting the nucleotide-specific conformational landscape of the functionally important C-terminus
AU - Czigleczki, Janka
AU - de Resende Lara, Pedro Tulio
AU - Dudas, Balint
AU - Jang, Hyunbum
AU - Perahia, David
AU - Nussinov, Ruth
AU - Balog, Erika
N1 - Publisher Copyright:
Copyright © 2023 Czigleczki, de Resende Lara, Dudas, Jang, Perahia, Nussinov and Balog.
PY - 2023/1/16
Y1 - 2023/1/16
N2 - 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.
AB - 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.
KW - C-terminus
KW - Ran
KW - aMDeNM
KW - conformational search
KW - conformational switch
KW - molecular dynamics
KW - normal modes
KW - small GTPase
UR - http://www.scopus.com/inward/record.url?scp=85147170872&partnerID=8YFLogxK
U2 - 10.3389/fmolb.2023.1111574
DO - 10.3389/fmolb.2023.1111574
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C2 - 36726377
AN - SCOPUS:85147170872
SN - 2296-889X
VL - 10
JO - Frontiers in Molecular Biosciences
JF - Frontiers in Molecular Biosciences
M1 - 1111574
ER -