Structural asymmetry in the closed state of mitochondrial Hsp90 (TRAP1) supports a two-step ATP hydrolysis mechanism.
Structural asymmetry in the closed state of mitochondrial Hsp90 (TRAP1) supports a two-step ATP hydrolysis mechanism.
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DOI：
10.1016/j.molcel.2013.12.023
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发表时间：
2014-01-23
期刊：
影响因子：
16
通讯作者：
Agard, David A.
中科院分区：
文献类型：
--
作者：
Lavery, Laura A.;Partridge, James R.;Ramelot, Theresa A.;Elnatan, Daniel;Kennedy, Michael A.;Agard, David A.
虽然结构对称性是同源寡聚蛋白质的一个普遍特征，但不对称性提供了独特的机制机会。我们介绍了全长TRAP1，线粒体Hsp90分子伴侣，在催化活性闭合状态下的晶体结构。TRAP1同源二聚体采用不同的不对称构象，其中一个原型通过在中间：C-末端结构域(MD：CTD)的螺旋交换而重新配置。重要的是，该接口在客户端绑定中起着关键作用。解决方法验证了不对称性，并显示了对Hsp90同源物的延伸。点突变破坏了每个MD：CTD界面上的独特接触，降低了催化活性和底物结合，并表明每个原型都需要获得两种构象。二聚体NTD：MD片段的结晶学数据表明，不对称是由NTD和CTD同时二聚化引起的应变引起的。观察到的不对称性为ATPase循环中的额外步骤提供了可能性，允许连续的ATP水解步骤来驱动客户重塑和客户释放。
While structural symmetry is a prevailing feature of homo-oligomeric proteins, asymmetry provides unique mechanistic opportunities. We present the crystal structure of full-length TRAP1, the mitochondrial Hsp90 molecular chaperone, in a catalytically active closed state. The TRAP1 homodimer adopts a distinct, asymmetric conformation, where one protomer is reconfigured via a helix swap at the Middle:C-terminal Domain (MD:CTD) interface. Importantly, this interface plays a critical role in client binding. Solution methods validate the asymmetry and show extension to Hsp90 homologs. Point mutations that disrupt unique contacts at each MD:CTD interface reduce catalytic activity, substrate binding, and demonstrate that each protomer needs access to both conformations. Crystallographic data on a dimeric NTD:MD fragment suggests that asymmetry arises from strain induced by simultaneous NTD and CTD dimerization. The observed asymmetry provides the potential for an additional step in the ATPase cycle, allowing sequential ATP hydrolysis steps to drive both client remodeling and client release.
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