<br>Rac1P29S 和 Rac1A159V 激活机制的差异,The Journal of Physical Chemistry B

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Rac1P29S 和 Rac1A159V 激活机制的差异
The Journal of Physical Chemistry B ( IF 2.8 ) Pub Date : 2021-04-13 , DOI: 10.1021/acs.jpcb.1c00883
Simge Senyuz ₁ , Hyunbum Jang ₂ , Ruth Nussinov _{2,

3} , Ozlem Keskin ₄ , Attila Gursoy ₅

Affiliation

Rac1 是一种小型 GTP 酶，在肌动蛋白重组、细胞运动、细胞存活/生长以及各种癌症类型和神经退行性疾病中发挥关键作用。与其他 Ras 超家族 GTP 酶类似，Rac1 在活性 GTP 结合状态和非活性 GDP 结合状态之间切换。开关 I 和 II 区域在 GDP/GTP 交换期间打开和关闭。 P29S 和 A159V（与 K-Ras ^A146旁系同源）突变是 Rac1 的两种最常见的体细胞突变。 Rac1 ^P29S是黑色素瘤的已知热点，而 Rac1 ^A159V最常见于头颈癌。为了研究这些取代如何诱导 Rac1 动力学，我们对处于 GTP 结合状态的野生型 Rac1 和两个突变系统（P29S 和 A159V）以及处于 GTP 结合状态的野生型 Rac1 和 P29S 突变系统进行了原子分子动力学模拟。 GDP约束状态。在这里，我们证明 P29S 和 A159V 突变以不同的机制激活 Rac1。在 Rac1 ^P29S -GTP 中，这种取代增加了基于 RMSF 和二面角计算的开关 I 的灵活性，并导致开放构象。我们认为开放的 Switch I 构象是 Rac1 ^P29S快速 GDP/GTP 交换的根本原因之一。另一方面，在Rac1 ^A159V -GTP中，GTP的鸟苷环与Rac1的一些接触暂时丢失，使得鸟苷环向开关I移动并随后关闭开关。 Rac1 ^A159V -GTP 采用 Ras 状态 2 样构象，其中两个开关区域均处于闭合构象，并且 Thr35 与核苷酸形成氢键。

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Mechanistic Differences of Activation of Rac1P29S and Rac1A159V

Rac1 is a small GTPase that plays key roles in actin reorganization, cell motility, and cell survival/growth as well as in various cancer types and neurodegenerative diseases. Similar to other Ras superfamily GTPases, Rac1 switches between active GTP-bound and inactive GDP-bound states. Switch I and II regions open and close during GDP/GTP exchange. P29S and A159V (paralogous to K-Ras^A146) mutations are the two most common somatic mutations of Rac1. Rac1^P29S is a known hotspot for melanoma, whereas Rac1^A159V most commonly occurs in head and neck cancer. To investigate how these substitutions induce the Rac1 dynamics, we used atomistic molecular dynamics simulations on the wild-type Rac1 and two mutant systems (P29S and A159V) in the GTP bound state, and on the wild-type Rac1 and P29S mutated system in the GDP bound state. Here, we show that P29S and A159V mutations activate Rac1 with different mechanisms. In Rac1^P29S-GTP, the substitution increases the flexibility of Switch I based on RMSF and dihedral angle calculations and leads to an open conformation. We propose that the open Switch I conformation is one of the underlying reasons for rapid GDP/GTP exchange of Rac1^P29S. On the other hand, in Rac1^A159V-GTP, some of the contacts of the guanosine ring of GTP with Rac1 are temporarily lost, enabling the guanosine ring to move toward Switch I and subsequently close the switch. Rac1^A159V-GTP adopts a Ras state 2 like conformation, where both switch regions are in closed conformation and Thr35 forms a hydrogen bond with the nucleotide.

更新日期：2021-04-22

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