Oncogenic mutations Q61L and Q61H confer active form-like structural features to the inactive state (state 1) conformation of H-Ras protein.

Biochemical and Biophysical Research Communications
Shigeyuki MatsumotoTohru Kataoka

Abstract

GTP-bound forms of Ras proteins (Ras•GTP) assume two interconverting conformations, "inactive" state 1 and "active" state 2. Our previous study on the crystal structure of the state 1 conformation of H-Ras in complex with guanosine 5'-(β, γ-imido)triphosphate (GppNHp) indicated that state 1 is stabilized by intramolecular hydrogen-bonding interactions formed by Gln61. Since Ras are constitutively activated by substitution mutations of Gln61, here we determine crystal structures of the state 1 conformation of H-Ras•GppNHp carrying representative mutations Q61L and Q61H to observe the effect of the mutations. The results show that these mutations alter the mode of hydrogen-bonding interactions of the residue 61 with Switch II residues and induce conformational destabilization of the neighboring regions. In particular, Q61L mutation results in acquirement of state 2-like structural features. Moreover, the mutations are likely to impair an intramolecular structural communication between Switch I and Switch II. Molecular dynamics simulations starting from these structures support the above observations. These findings may give a new insight into the molecular mechanism underlying the aberrant activation of the Gln61 mutants.

References

Apr 30, 2004·Journal of Computational Chemistry·Junmei WangDavid A Case
Jun 24, 2008·Nature Reviews. Molecular Cell Biology·Antoine E Karnoub, Robert A Weinberg
Apr 13, 2010·Acta Crystallographica. Section D, Biological Crystallography·P EmsleyK Cowtan
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·Martyn D WinnKeith S Wilson
May 17, 2012·Cancer Research·Ian A PriorCarla Mattos
Jul 25, 2012·BMC Research Notes·Alan W Sousa da Silva, Wim F Vranken
Sep 4, 2013·Acta Crystallographica. Section D, Biological Crystallography·Seiki BabaTakashi Kumasaka
Feb 17, 2015·Structure·Susan K FeticsCarla Mattos
May 6, 2015·Proceedings of the National Academy of Sciences of the United States of America·Mohammad T Mazhab-JafariMitsuhiko Ikura
Mar 8, 2016·Journal of Chemical Theory and Computation·Stefan DoerrGianni De Fabritiis
Jan 1, 1997·Methods in Enzymology·Zbyszek Otwinowski, Wladek Minor
Dec 1, 2000·Angewandte Chemie·Alfred Wittinghofer, Herbert Waldmann
Oct 8, 2019·Acta Crystallographica. Section D, Structural Biology·Dorothee LiebschnerPaul D Adams
Jul 19, 2020·Biophysical Journal·Shigeyuki MatsumotoYasushi Okuno

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