A Highly Strained Nuclear Conformation of the Exportin Cse1p Revealed by Molecular Dynamics Simulations

TY - JOUR

T1 - A Highly Strained Nuclear Conformation of the Exportin Cse1p Revealed by Molecular Dynamics Simulations

AU - Zachariae, Ulrich

AU - Grubmüller, Helmut

N1 - Funding Information: We thank Dirk Görlich, Peter Hinterdorfer, Ziv Reich, Matthias Müller, Carsten Kutzner, and Marcus Kubitzki for stimulating discussions. This work was supported by the Human Frontier Science Program (Grant RGP 53/2004). Copyright: © 2006 Elsevier Ltd. All rights reserved.

PY - 2006/9

Y1 - 2006/9

N2 - To investigate the stability of the open nuclear state of the exportin Cse1p and its closing mechanism at the atomic level, we have performed multiple molecular dynamics simulations. The simulations revealed a strikingly fast transition of Cse1p from the open conformation to the closed cytoplasmic form, consistent with the proposal that Cse1p represents a "spring-loaded molecule." The structure of the ring-shaped state obtained in the simulations is remarkably close to the crystal structure of the cytoplasmic state, though the open nuclear structure was used as the only input. The conformational change is initially driven by release of strain due to RanGTP/importin-α binding. Subsequently, a stable closed state is formed, driven by attraction of electrostatically complementary interfaces. These results are consistent with and extend previous proposals. Reverse-charge and neutral mutants remained in an open state. The simulations predict a detailed reaction pathway and resolve the role of suggested hinge regions.

AB - To investigate the stability of the open nuclear state of the exportin Cse1p and its closing mechanism at the atomic level, we have performed multiple molecular dynamics simulations. The simulations revealed a strikingly fast transition of Cse1p from the open conformation to the closed cytoplasmic form, consistent with the proposal that Cse1p represents a "spring-loaded molecule." The structure of the ring-shaped state obtained in the simulations is remarkably close to the crystal structure of the cytoplasmic state, though the open nuclear structure was used as the only input. The conformational change is initially driven by release of strain due to RanGTP/importin-α binding. Subsequently, a stable closed state is formed, driven by attraction of electrostatically complementary interfaces. These results are consistent with and extend previous proposals. Reverse-charge and neutral mutants remained in an open state. The simulations predict a detailed reaction pathway and resolve the role of suggested hinge regions.

UR - https://www.scopus.com/pages/publications/33748305808

U2 - 10.1016/j.str.2006.08.001

DO - 10.1016/j.str.2006.08.001

M3 - Article

C2 - 16962977

AN - SCOPUS:33748305808

SN - 0969-2126

VL - 14

SP - 1469

EP - 1478

JO - Structure

JF - Structure

IS - 9

ER -