University of Colorado Anschutz Medical Campus, Department of Biochemistry and Molecular Genetics, Aurora, CO, USA.
Laboratory of Physical Chemistry, Department of Chemistry and Applied Biosciences, ETH Zürich, Vladimir-Prelog-Weg 2, ETH-Hönggerberg, Zürich, Switzerland.
Nat Commun. 2022 Aug 4;13(1):4546. doi: 10.1038/s41467-022-32340-x.
Pin1 is a two-domain cell regulator that isomerizes peptidyl-prolines. The catalytic domain (PPIase) and the other ligand-binding domain (WW) sample extended and compact conformations. Ligand binding changes the equilibrium of the interdomain conformations, but the conformational changes that lead to the altered domain sampling were unknown. Prior evidence has supported an interdomain allosteric mechanism. We recently introduced a magnetic resonance-based protocol that allowed us to determine the coupling of intra- and interdomain structural sampling in apo Pin1. Here, we describe ligand-specific conformational changes that occur upon binding of pCDC25c and FFpSPR. pCDC25c binding doubles the population of the extended states compared to the virtually identical populations of the apo and FFpSPR-bound forms. pCDC25c binding to the WW domain triggers conformational changes to propagate via the interdomain interface to the catalytic site, while FFpSPR binding displaces a helix in the PPIase that leads to repositioning of the PPIase catalytic loop.
Pin1 是一种具有两个结构域的细胞调节因子，能够使肽脯氨酸异构化。其催化结构域（PPIase）和另一个配体结合结构域（WW）可分别采取伸展和紧凑的构象。配体结合会改变结构域间构象的平衡，但导致结构域构象发生改变的构象变化尚不清楚。先前的证据支持结构域间变构机制。我们最近引入了一种基于磁共振的方案，该方案允许我们确定 apo Pin1 中结构域内和结构域间结构采样的耦合。在这里，我们描述了结合 pCDC25c 和 FFpSPR 时发生的配体特异性构象变化。与 apo 和 FFpSPR 结合形式的几乎相同的构象相比，pCDC25c 的结合使伸展状态的比例增加了一倍。pCDC25c 与 WW 结构域的结合引发构象变化，通过结构域界面传播至催化位点，而 FFpSPR 结合会置换 PPIase 中的一个螺旋，导致 PPIase 催化环重新定位。
