Conformational Rearrangements to the Intracellular Open States of the LeuT and ApcT Transporters Are Modulated by Common Mechanisms
Conformational Rearrangements to the Intracellular Open States of the LeuT and ApcT Transporters Are Modulated by Common Mechanisms
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DOI：
10.1016/j.bpj.2010.10.003
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发表时间：
2010-12-15
影响因子：
3.4
通讯作者：
Weinstein, Harel
中科院分区：
文献类型：
--
作者：
Shi, Lei;Weinstein, Harel
最近的晶体学研究表明，五个转运蛋白家族之间没有太多的序列相似性，有类似的结构折叠LeuT，细菌神经递质：钠同向转运蛋白同系物。LeuT褶皱的特征在于内部双重结构伪对称性。这些家族中的一些成员的转运循环依赖于跨膜的钠梯度，而在另一些家族中，钠的作用被质子模仿。我们报告的识别与LeuT折叠，这是可识别的功能相关的构象转变的转运蛋白的常见结构动力学元素。来自氨基酸-多胺-有机转运蛋白家族的LeuT和ApcT的比较计算建模和模拟研究的结果定义了Na（+）结合与转运过程偶联的分子内机制，并挑选出TM 1a在向内开放构象转变中的主导/活性作用。这些机制的见解是在LeuT动力学与单分子荧光和模拟，产生了良好的协议的动态细节的协作调查的背景下得出的，并被发现是概括整个转运蛋白家族和超越序列和基序的相似性。
Recent crystallographic studies revealed that five transporter families without much sequence similarities among them have similar structure folds to LeuT, a bacterial neurotransmitter:sodium symporter homolog. The LeuT fold is characterized by an internal twofold structural pseudosymmetry. The transport cycle of some members of each of these families is dependent on a sodium gradient across the membrane, whereas in some others the role of sodium is mimicked by proton. We report on the identification of common structure-dynamics elements of the transporters with LeuT fold, which are recognizable in the conformational transitions related to function. The findings from comparative computational modeling and simulation studies of LeuT, and ApcT from the amino acid-polyamine-organocation transporter family define the intramolecular mechanisms by which Na(+) binding couples to the transport process, and single out the lead/active role of TM1a in the transition to inward-open conformation. These mechanistic insights are derived in the context of collaborative investigations of LeuT dynamics with both single-molecule fluorescence and simulations that have produced excellent agreement of the dynamic details, and are found to be generalizable across the transporter families and to transcend sequence and motif similarities.