Allostery in Hsp70 chaperones is transduced by subdomain rotations.
Allostery in Hsp70 chaperones is transduced by subdomain rotations.
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DOI：
10.1016/j.jmb.2009.01.062
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发表时间：
2009-05-08
影响因子：
5.6
通讯作者：
Zuiderweg, Erik R. P.
中科院分区：
文献类型：
--
作者：
Bhattacharya, Akash;Kurochkin, Alexander V.;Yip, Grover N. B.;Zhang, Yongbo;Bertelsen, Eric B.;Zuiderweg, Erik R. P.
热休克蛋白70是核心的蛋白质折叠，重折叠，和运输的生物体，从古人类，在正常和应激细胞条件下。Hsp 70由核苷酸结合结构域（NBD）和底物结合结构域（SBD）组成。NBD中的核苷酸结合位点和SBD中的底物结合位点是变构连接的：ADP结合促进底物结合，而ATP结合促进底物释放。Hsp 70与细胞凋亡的抑制有关，即，癌症和与蛋白质错误折叠相关的疾病，如阿尔茨海默氏症、帕金森氏症和亨廷顿氏症。它一直是一个目标，以表征这些蛋白质的变构偶联的性质。然而，早期的研究分离的NBD不能显示ATP和ADP状态之间的整体构象的任何差异。因此，问题是：NBD和SBD之间的核苷酸状态是如何传递的？在这里，我们报告的44 kDa的NBD的热栖热菌的热休克蛋白70在ADP和AMP-PNP状态的溶液NMR研究。使用溶液NMR方法的残余偶极耦合分析，我们确定，发生显着的旋转后，交换核苷酸的NBD的不同子域。在不存在核苷酸交换因子的情况下，这些旋转调节对核苷酸结合裂缝的接近。此外，旋转引起的变化，在可及性的疏水表面裂缝远离核苷酸结合位点，这以前已被确定为必不可少的NBD和SBD之间的变构通信。我们建议，这是在NBD表面裂缝的变化，构成了变构信号，可以识别的SBD。
Hsp70s are central to protein folding, refolding, and trafficking in organisms ranging from Archae to Homo sapiens, both at normal and at stressed cellular conditions. Hsp70s are comprised of a nucleotide-binding domain (NBD), and a substrate-binding domain (SBD). The nucleotide binding site in the NBD and the substrate binding site in the SBD are allosterically linked: ADP binding promotes substrate binding, while ATP binding promotes substrate release. Hsp70s have been linked to inhibition of apoptosis, i.e., cancer, and diseases associated with protein misfolding such as Alzheimer’s, Parkinson’s, and Huntington’s. It has long been a goal to characterize the nature of the allosteric coupling in these proteins. However, earlier studies of the isolated NBD could not show any difference in overall conformation between the ATP and ADP state. Hence the question: how is the state of the nucleotide communicated between NBD and SBD? Here we report a solution NMR study of the 44 kDa NBD of the Hsp70 from Thermus thermophilus, in the ADP and AMP-PNP states. Using the solution NMR methods of residual dipolar coupling analysis, we determine that significant rotations occur for the different subdomains of the NBD upon exchange of nucleotide. These rotations modulate the access to the nucleotide binding cleft, in absence of a nucleotide exchange factor. Moreover, the rotations cause a change in accessibility of a hydrophobic surface cleft remote from the nucleotide binding site, which previously has been identified as essential to the allosteric communication between NBD and SBD. We propose that it is this change in the NBD surface cleft that constitutes the allosteric signal that can be recognized by the SBD.
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影响因子：
2.2
作者：
Ottiger, M;Delaglio, F;Bax, A
通讯作者：
Bax, A
DOI：
10.1073/pnas.0903503106
发表时间：
2009-05-26
影响因子：
11.1
作者：
Bertelsen, Eric B.;Chang, Lyra;Zuiderweg, Erik R. P.
通讯作者：
Zuiderweg, Erik R. P.
影响因子：
2.9
作者：
MORSHAUSER, RC;WANG, H;ZUIDERWEG, ERP
通讯作者：
ZUIDERWEG, ERP
影响因子：
5.6
作者：
Morshauser, RC;Hu, WD;Zuiderweg, ERP
通讯作者：
Zuiderweg, ERP
影响因子：
4.8
作者：
OBrien, MC;Flaherty, KM;McKay, DB
通讯作者：
McKay, DB