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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Entropic switch regulates myristate exposure in the HIV-1 matrix protein
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Entropic switch regulates myristate exposure in the HIV-1 matrix protein

机译：熵开关调节HIV-1基质蛋白中肉豆蔻酸的暴露

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摘要

The myristoylated matrix protein (myr-MA) of HIV functions as a regulator of intracellular localization, targeting the Gag precursor polyprotein to lipid rafts in the plasma membrane during virus assembly and dissociating from the membrane during infectivity for nuclear targeting of the preintegration complex. Membrane release is triggered by proteolytic cleavage of Gag, and it has, until now, been believed that proteolysis induces a conformational change in myr-MA that sequesters the myristyl group. NMR studies reported here reveal that myr-MA adopts myr-exposed [myr(e)] and -sequestered [myr(s)] states, as anticipated. Unexpectedly, the tertiary structures of the protein in both states are very similar, with the sequestered myristyl group occupying a cavity that requires only minor conformational adjustments for insertion. In addition, myristate exposure is coupled with trimerization, with the myristyl group sequestered in the monomer and exposed in the trimer (K_(assoc) = 2.5 +- 0.6 x 10~8 M~(-2)). The equilibrium constant is shifted ≈20-fold toward the trimeric, myristate-exposed species in a Gag-like construct that includes the capsid domain, indicating that exposure is enhanced by Gag subdomains that promote self-association. Our findings indicate that the HIV-1 myristyl switch is regulated not by mechanically induced conformational changes, as observed for other myristyl switches, but instead by entropic modulation of a preexisting equilibrium.
机译：HIV的豆蔻酰化基质蛋白（myr-MA）充当细胞内定位的调节剂，在病毒组装过程中将Gag前体多蛋白靶向质膜​​中的脂质筏，并在感染前从膜上解离，以对整合前复合物进行核靶向。膜的释放是由Gag的蛋白水解切割触发的，迄今为止，人们一直认为蛋白水解会诱导myr-MA的构象变化，从而使肉豆蔻基团隔离。此处报道的NMR研究表明，myr-MA具有预期的myr暴露[myr（e）]和-异位[myr（s）]状态。出乎意料的是，在两种状态下，蛋白质的三级结构都非常相似，螯合的肉豆蔻基占据了一个空腔，该空腔仅需进行微小的构象调整即可插入。另外，肉豆蔻酸酯暴露与三聚化相结合，肉豆蔻酰基被螯合在单体中并在三聚体中暴露（K_（缔合）＝ 2.5±0.6×10-8M（-2））。在包括衣壳结构域的Gag样结构中，平衡常数向三聚体，肉豆蔻酸酯暴露的物种偏移≈20倍，这表明通过促进自我缔合的Gag子域增强了暴露。我们的发现表明，HIV-1肉豆蔻酰开关不受机械诱导的构象变化（如其他肉豆蔻酰开关所观察到）的调节，而是由预先存在的平衡的熵调节来调节。

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