TY - JOUR
T1 - Allosteric effects of the oncogenic rasq61l mutant on raf-RBD
AU - Fetics, Susan K.
AU - Guterres, Hugo
AU - Kearney, Bradley M.
AU - Buhrman, Greg
AU - Ma, Buyong
AU - Nussinov, Ruth
AU - Mattos, Carla
N1 - Publisher Copyright:
©2015 Elsevier Ltd. All rights reserved.
PY - 2015/3/3
Y1 - 2015/3/3
N2 - The Ras/Raf/MEK/ERK signal transduction pathway is a major regulator of cell proliferation activated by Ras-guanosine triphosphate (GTP). The oncogenic mutant RasQ61L is not able to hydrolyze GTP in the presence of Raf and thus is a constitutive activator of this mitogenic pathway. The Ras/Raf interaction is essential for the activation of the Raf kinase domain through a currently unknown mechanism. We present the crystal structures of the Ras-GppNHp/Raf-RBD and RasQ61L-GppNHp/Raf-RBD complexes, which, in combination with MD simulations, reveal differences in allosteric interactions leading from the Ras/Raf interface to the Ras calcium-binding site and to the remote Raf-RBD loop L4. In the presence of Raf, the RasQ61L mutant has a rigid switch II relative to the wild-type and increased flexibility at the interface with switch I, which propagates across Raf-RBD. We show that in addition to local perturbations on Ras, RasQ61L has substantial long-range effects on the Ras allosteric lobe and on Raf-RBD.
AB - The Ras/Raf/MEK/ERK signal transduction pathway is a major regulator of cell proliferation activated by Ras-guanosine triphosphate (GTP). The oncogenic mutant RasQ61L is not able to hydrolyze GTP in the presence of Raf and thus is a constitutive activator of this mitogenic pathway. The Ras/Raf interaction is essential for the activation of the Raf kinase domain through a currently unknown mechanism. We present the crystal structures of the Ras-GppNHp/Raf-RBD and RasQ61L-GppNHp/Raf-RBD complexes, which, in combination with MD simulations, reveal differences in allosteric interactions leading from the Ras/Raf interface to the Ras calcium-binding site and to the remote Raf-RBD loop L4. In the presence of Raf, the RasQ61L mutant has a rigid switch II relative to the wild-type and increased flexibility at the interface with switch I, which propagates across Raf-RBD. We show that in addition to local perturbations on Ras, RasQ61L has substantial long-range effects on the Ras allosteric lobe and on Raf-RBD.
UR - http://www.scopus.com/inward/record.url?scp=84923853645&partnerID=8YFLogxK
U2 - 10.1016/j.str.2014.12.017
DO - 10.1016/j.str.2014.12.017
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C2 - 25684575
AN - SCOPUS:84923853645
SN - 0969-2126
VL - 23
SP - 505
EP - 516
JO - Structure
JF - Structure
IS - 3
ER -