Department of Chemistry and Biochemistry, and Center for Theoretical Biological Physics, University of California at San Diego, La Jolla, CA 92093, USA.
Proc Natl Acad Sci U S A. 2012 Feb 7;109(6):1955-60. doi: 10.1073/pnas.1116369109. Epub 2012 Jan 23.
MitoNEET is a recently identified diabetes drug target that coordinates a transferable 2Fe-2S cluster, and additionally contains an unusual strand swap. In this manuscript, we use a dual basin structure-based model to predict and characterize the folding and functionality of strand swapping in mitoNEET. We demonstrate that a strand unswapped conformation is kinetically accessible and that multiple levels of control are employed to regulate the conformational dynamics of the system. Environmental factors such as temperature can shift route preference toward the unswapped pathway. Additionally we see that a region recently identified as contributing to frustration in folding acts as a regulatory hinge loop that modulates conformational balance. Interestingly, strand unswapping transfers strain specifically to cluster-coordinating residues, opening the cluster-coordinating pocket. Strengthening contacts within the cluster-coordinating pocket opens a new pathway between the swapped and unswapped conformation that utilizes cracking to bypass the unfolded basin. These results suggest that local control within distinct regions affect motions important in regulating mitoNEET's 2Fe-2S clusters.
MitoNEET 是一个最近被确定的糖尿病药物靶点，它协调可转移的 2Fe-2S 簇，并且还含有一个不寻常的链交换。在本手稿中，我们使用基于双盆地结构的模型来预测和表征 mitoNEET 中链交换的折叠和功能。我们证明了无链交换构象在动力学上是可及的，并且采用了多个层次的控制来调节系统的构象动力学。环境因素，如温度，可以改变无链交换途径的偏好。此外，我们发现最近被确定为对折叠产生干扰的区域充当调节铰链环，调节构象平衡。有趣的是，链交换将应变专门传递给簇协调残基，打开簇协调口袋。在簇协调口袋内加强接触，在交换和未交换构象之间打开一个新的途径，该途径利用破解绕过未折叠的盆地。这些结果表明，不同区域内的局部控制会影响调节 mitoNEET 的 2Fe-2S 簇的重要运动。
