Aha1 Exhibits Distinctive Dynamics Behavior and Chaperone-Like Activity.
Aha1 Exhibits Distinctive Dynamics Behavior and Chaperone-Like Activity.
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Aha1 表现出独特的动力学行为和类似伴侣的活动
DOI：
10.3390/molecules26071943
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发表时间：
2021-03-30
期刊：
影响因子：
--
通讯作者：
Zhang N
中科院分区：
文献类型：
--
作者：
Hu H;Wang Q;Du J;Liu Z;Ding Y;Xue H;Zhou C;Feng L;Zhang N
AHA1是已知的唯一能强烈刺激Hsp90 ATPase活性的辅助伴侣。同时，除了已被充分研究的辅助伴侣功能外，人类AHA1还被证明具有对抗应激变性蛋白的伴侣活性。为了更好地了解AHA1的S辅助伴侣和伴侣样活性，利用核磁共振技术揭示了全长人AHA1独特的结构和内部动力学特征。然后我们发现，在溶液中，AHA1的两个结构域都表现出不同的热稳定性和动力学行为，这些行为由它们的一级序列和三维结构决定。AHA1‘S N-末端结构域(AHA1N)的热稳定性较低(熔融温度为AH128-162：54.45°C)，在µS-ms时间尺度上表现出缓慢运动的内部动力学特征。上述实验结果表明，AHA1N处于不利于能量的状态，因此在恒温条件下有利于AHA1N与其伴侣蛋白如HSP90‘S中间域的相互作用。与AHA1N不同，AHA1C(AHA1‘S C-末端结构域)具有更高的热稳定性(AHA1204-335的熔化温度：72.41°C)和在PS-ns时间尺度上具有中间运动的内部动力学特征。AHA1C的热稳定性和结构稳定性使其能够稳定二聚化的HSP90‘S N末端结构域的疏水沟槽。值得注意的是，根据核磁共振数据和热位移结果，尽管非常N-末端区域(M1-W27)和C-末端松弛素样因子(RLf)基序与人AHA1的其余部分没有紧密接触，但它们被确定在识别内在无序的病理性α-突触核蛋白中发挥重要作用。
Aha1 is the only co-chaperone known to strongly stimulate the ATPase activity of Hsp90. Meanwhile, besides the well-studied co-chaperone function, human Aha1 has also been demonstrated to exhibit chaperoning activity against stress-denatured proteins. To provide structural insights for a better understanding of Aha1’s co-chaperone and chaperone-like activities, nuclear magnetic resonance (NMR) techniques were used to reveal the unique structure and internal dynamics features of full-length human Aha1. We then found that, in solution, both the two domains of Aha1 presented distinctive thermal stabilities and dynamics behaviors defined by their primary sequences and three-dimensional structures. The low thermal stability (melting temperature of Aha128–162: 54.45 °C) and the internal dynamics featured with slow motions on the µs-ms time scale were detected for Aha1’s N-terminal domain (Aha1N). The aforementioned experimental results suggest that Aha1N is in an energy-unfavorable state, which would therefore thermostatically favor the interaction of Aha1N with its partner proteins such as Hsp90’s middle domain. Differently from Aha1N, Aha1C (Aha1’s C-terminal domain) exhibited enhanced thermal stability (melting temperature of Aha1204–335: 72.41 °C) and the internal dynamics featured with intermediate motions on the ps-ns time scale. Aha1C’s thermal and structural stabilities make it competent for the stabilization of the exposed hydrophobic groove of dimerized Hsp90’s N-terminal domain. Of note, according to the NMR data and the thermal shift results, although the very N-terminal region (M1-W27) and the C-terminal relaxin-like factor (RLF) motif showed no tight contacts with the remaining parts of human Aha1, they were identified to play important roles in the recognition of intrinsically disordered pathological α-synuclein.
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