论文标题
MCL-1滥交及其具有约束力伙伴的结构弹性
MCL-1 promiscuity and the structural resilience of its binding partners
论文作者
论文摘要
MCL-1及其天然抑制剂，仅BH3蛋白PUMA，BIM和NOXA通过在纠缠的结合网络中混杂相互作用来调节凋亡。关于瞬态过程和动态构象波动知之甚少，这是仅MCL-1/BH3复合物的形成和稳定性的基础。在这项研究中，我们设计了MCL-1/PUMA和MCL-1/NOXA的可拍照版本，并在具有瞬态红外光谱的超快光扰动后研究了蛋白质反应。在所有情况下，我们都观察到部分$α$ helical的展开，尽管在较大的时间尺度上（PUMA的1.6〜NS，先前研究的BIM的9.7〜NS，NOXA的85〜NS）。这些差异被解释为仅BH3特异性的“结构弹性”，以违抗扰动，同时留在Mcl-1的结合口袋中。因此，提出的见解可以帮助更好地了解PUMA，BIM和NOXA，MCL-1的滥交以及蛋白质在凋亡网络中的作用。
MCL-1 and its natural inhibitors, the BH3-only proteins PUMA, BIM, and NOXA regulate apoptosis by interacting promiscuously within an entangled binding network. Little is known about the transient processes and dynamic conformational fluctuations that are the basis for the formation and stability of the MCL-1/BH3-only complex. In this study, we designed photoswitchable versions of MCL-1/PUMA and MCL-1/NOXA, and investigated the protein response after an ultrafast photo-perturbation with transient infrared spectroscopy. We observed partial $α$-helical unfolding in all cases, albeit on strongly varying timescales (1.6~ns for PUMA, 9.7~ns for the previously studied BIM, and 85~ns for NOXA). These differences are interpreted as a BH3-only-specific "structural resilience" to defy the perturbation while remaining in MCL-1's binding pocket. Thus, the presented insights could help to better understand the differences between PUMA, BIM, and NOXA, the promiscuity of MCL-1 in general, and the role of the proteins in the apoptotic network.
