Open AccessComparison of the Conformations of KRAS Isoforms, K-Ras4A and K-Ras4B, Points to Similarities and Significant Differences
Author(s) -
Mayukh Chakrabarti,
Hyunbum Jang,
Ruth Nussinov
Publication year - 2016
Publication title -
the journal of physical chemistry. b
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.864
H-Index - 392
eISSN - 1520-6106
pISSN - 1520-5207
DOI - 10.1021/acs.jpcb.5b11110
Subject(s) - kras , hras , gene isoform , neuroblastoma ras viral oncogene homolog , splice , gtpase , chemistry , mutation , genetics , biology , gene
Human HRAS, KRAS, and NRAS genes encode four isoforms of Ras, a p21 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 (G151R/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; both factors 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.