Chakrabarti, Mayukh; Jang, Hyunbum; Nussinov, Ruth
Comparison of the Conformations of KRAS Isoforms, K-Ras4A and K-Ras4B, Points to Similarities and Significant Differences
JOURNAL OF PHYSICAL CHEMISTRY B, 120:667-679, FEB 4 2016

Human HRAS, KRAS, and NRAS genes encode four isoforms of Ras, a p2,1 GTPase. Mutations in KRAS account for the majority of RAS-driven cancers. The KRAS has two splice variants, K-Ras4A and K-Ras4B. Due to their reversible palmitoylation, K-Ras4A and N-Ras have bimodal signaling states. K-Ras4A and K-Ras4B differ in four catalytic domain residues (G1S1R/D153E/K165Q/H166Y) and in their disordered C-terminal hypervariable region (HVR). In K-Ras4A, the HVR is not as strongly positively charged as in K-Ras4B (+6e vs +9e). Here, we performed all-atom molecular dynamics simulations to elucidate isoform-specific differences between the two splice variants. We observe that the catalytic domain of GDP-bound K-Ras4A has a more exposed nucleotide binding pocket than K-Ras4B, and the dynamic fluctuations in switch I and II regions also differ; may influence guanine nucleotide exchange. We further observe that like K-Kas4B, full-length K-Ras4A exhibits nucleotide dependent HVR fluctuations; however, these fluctuations differ between the GDP-bound forms of K-Ras4A and K-Ras4B. Unlike K-Ras4B where the HVR tends to cover the effector binding region, in K-Ras4A, autoinhibited states are unstable. With lesser charge, the K-Ras4A HVR collapses on itself, making it less available for binding the catalytic domain. Since the HVRs of N- and H-Ras are weakly charged (+1e and +2e, respectively), autoinhibition may be a unique feature of K-Ras4B.

DOI:10.1021/acs.jpcb.5b11110

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