Electrostatically accelerated coupled binding and folding of intrinsically disordered proteins.
Electrostatically accelerated coupled binding and folding of intrinsically disordered proteins.
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DOI：
10.1016/j.jmb.2012.06.019
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发表时间：
2012-10-05
影响因子：
5.6
通讯作者：
Chen, Jianhan
中科院分区：
文献类型：
--
作者：
Ganguly, Debabani;Otieno, Steve;Waddell, Brett;Iconaru, Luigi;Kriwacki, Richard W.;Chen, Jianhan
固有无序蛋白(IDPs)现在被认为在生物学中普遍存在，并且已经讨论了许多潜在的功能益处。然而，在IDPs的特定相互作用中经常需要肽折叠可能会造成动力学瓶颈，只有在相遇时有效折叠才能克服这一瓶颈。有趣的是，现有的动力学数据表明，IDPs的特异性结合通常不比球状蛋白慢。在这里，我们利用细胞周期调控因子p27Kip1(P27)作为模型系统，以了解IdPs如何在遇到时实现有效的折叠以便于识别。结合实验和粗粒度模拟，我们证明了p27上丰富的电荷与其在Cyclin A上结合位置附近的远程静电相互作用不仅提高了相遇几率(即静电转向)，而且还促进了相遇复合体中的折叠能力拓扑，从而允许随后在通往特定复合体的途中快速形成短程天然相互作用。相反，非特异性疏水相互作用虽然几乎不影响相遇几率，但会显著降低相遇时折叠的效率，并导致结合动力学变慢。进一步分析一组已知的IdP络合物中的电荷分布表明，尽管IdP结合部位往往比靶表面的其余部分更疏水，但它们附近经常富含电荷以补充IdP上的结合部位。这一观察表明，静电加速的相遇和诱导折叠可能是促进简易IDP识别的一种普遍机制。
Intrinsically disordered proteins (IDPs) are now recognized to be prevalent in biology, and many potential functional benefits have been discussed. However, the frequent requirement of peptide folding in specific interactions of IDPs could impose a kinetic bottleneck, which could be overcome only by efficient folding upon encounter. Intriguingly, existing kinetic data suggest that specific binding of IDPs is generally no slower than that of globular proteins. Here, we exploited the cell cycle regulator p27Kip1 (p27) as a model system to understand how IDPs might achieve efficient folding upon encounter for facile recognition. Combining experiments and coarse-grained modeling, we demonstrate that long-range electrostatic interactions between enriched charges on p27 and near its binding site on cyclin A not only enhance the encounter rate (i.e., electrostatic steering), but also promote folding-competent topologies in the encounter complexes, allowing rapid subsequent formation of short-range native interactions en route to the specific complex. In contrast, nonspecific hydrophobic interactions, while hardly affecting the encounter rate, can significantly reduce the efficiency of folding upon encounter and lead to slower binding kinetics. Further analysis of charge distributions in a set of known IDP complexes reveals that, although IDP binding sites tend to be more hydrophobic compared to the rest of the target surface, their vicinities are frequently enriched with charges to complement those on IDPs. This observation suggests that electrostatically accelerated encounter and induced folding might represent a prevalent mechanism for promoting facile IDP recognition.
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影响因子：
6.8
作者：
Eliezer, David
通讯作者：
Eliezer, David
影响因子：
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作者：
Dunker, AK;Lawson, JD;Obradovic, Z
通讯作者：
Obradovic, Z
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作者：
Bienkiewicz, EA;Adkins, JN;Lumb, KJ
通讯作者：
Lumb, KJ
影响因子：
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作者：
Ganguly, Debabani;Zhang, Weihong;Chen, Jianhan
通讯作者：
Chen, Jianhan
影响因子：
3
作者：
BROOKS, BR;BRUCCOLERI, RE;KARPLUS, M
通讯作者：
KARPLUS, M