Comparison of the Conformations of KRAS Isoforms, K-Ras4A and K-Ras4B, Points to Similarities and Significant Differences.
Comparison of the Conformations of KRAS Isoforms, K-Ras4A and K-Ras4B, Points to Similarities and Significant Differences.
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DOI：
10.1021/acs.jpcb.5b11110
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发表时间：
2016-02-04
期刊：
影响因子：
--
通讯作者：
Nussinov R
中科院分区：
文献类型：
--
作者：
Chakrabarti M;Jang H;Nussinov R
人HRAS、KRAS和NRAS基因编码Ras的四种同种型，Ras是一种p21 GT3。KRAS中的突变占大多数RAS驱动的癌症。KRAS有两种剪接变体，K-Ras 4A和K-Ras 4 B。由于其可逆的棕榈酰化，K-Ras 4A和N-Ras具有双峰信号传导状态。K-Ras 4A和K-Ras 4 B在四个催化结构域残基（G151 R/D153 E/K165 Q/H166 Y）和它们的无序C-末端高变区（HVR）中不同。在K-Ras 4A中，HVR不像K-Ras 4 B中那样带强正电荷（+6e vs +9e）。在这里，我们进行了全原子分子动力学模拟，以阐明两个剪接变体之间的异构体特异性差异。我们观察到GDP结合K-Ras 4A的催化结构域具有比K-Ras 4 B更暴露的核苷酸结合口袋，并且开关I和II区域的动态波动也不同;这两个因素都可能影响鸟嘌呤-核苷酸交换。我们进一步观察到，像K-Kas 4 B一样，全长K-Ras 4A表现出核苷酸依赖性HVR波动;然而，这些波动在K-Ras 4A和K-Ras 4 B的GDP结合形式之间不同。与HVR倾向于覆盖效应物结合区域的K-Ras 4 B不同，在K-Ras 4A中，自抑制状态是不稳定的。由于电荷较少，K-Ras 4A HVR自身塌陷，使其不太可用于结合催化结构域。由于N-Ras和H-Ras的HVR带弱电荷（分别为+1e和+2e），因此自抑制可能是K-Ras 4 B的独特特征。
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.
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DOI：
10.1038/nrm3255
发表时间：
2011-12-22
期刊：
Nature reviews. Molecular cell biology
影响因子：
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作者：
通讯作者：
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影响因子：
4.8
作者：
Ford, B;Skowronek, K;Nassar, N
通讯作者：
Nassar, N
影响因子：
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作者：
Arozarena, Imanol;Calvo, Fernando;Crespo, Piero
通讯作者：
Crespo, Piero
影响因子：
4.8
作者：
Clyde-Smith, J;Silins, G;Hancock, JF
通讯作者：
Hancock, JF
影响因子：
5.8
作者：
Eargle, John;Luthey-Schulten, Zaida
通讯作者：
Luthey-Schulten, Zaida