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

Biochem Biophys Res Commun. 2021 Jun 5;565:85-90. doi: 10.1016/j.bbrc.2021.05.084. Online ahead of print.ABSTRACTGTP-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.PMID:34102474 | DOI:10.1016/j.bbrc.2021.05.084

Source: Biochemical and Biophysical Research communications - June 8, 2021 Category: Biochemistry Authors: Shigeyuki Matsumoto Haruka Taniguchi-Tamura Mitsugu Araki Takashi Kawamura Ryo Miyamoto Chiemi Tsuda Fumi Shima Takashi Kumasaka Yasushi Okuno Tohru Kataoka Source Type: research