Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Hiroshima 739-8526, Japan.
Biochemistry. 2022 Jun 21;61(12):1167-1180. doi: 10.1021/acs.biochem.2c00255. Epub 2022 Jun 1.
Peptides mediate the interdomain communication of Pin1 (peptidyl-prolyl isomerase) and can regulate its conformation and biochemical functions, providing an idea for drug design using Pin1. Two template peptide sequences have been widely used in the extended or compact state of Pin1 (Cdc25C, E-Q-P-L-pT-P-V-T-D-L; Pintide, W-F-Y-pS-P-R). The way in which specific pSer/Thr-Pro peptides regulate interdomain communication to achieve the opposite state is not clear. In this study, we subdivided the sequence composition of eight types of modified peptides and investigated the interaction with Pin1 by solution nuclear magnetic resonance and molecular dynamics. Demonstrating sequence dependence on the pSer-Pro or pThr-Pro motif and different residues in anchoring the WW domain, the Pin peptide (Pintide, PintideT, Pin25C, and Pin25CT) transmits this concentration accumulation to the PPIase domain, thus exhibiting two anchoring tendencies. However, the Cdc peptide (Cdc25C, Cdc25CS, Cdctide, and CdctideS) has a low binding energy that makes it difficult for the conformation to reach a steady state. In addition, Pin1 is influenced by both compact and extended states, regulated precisely by the sequence as well as by threonine or serine. These results provide new insight into the interdomain communication of Pin1 via pSer/Thr-Pro peptide binding.
肽介导 Pin1（肽基脯氨酰顺反异构酶）的结构域间通讯，并可以调节其构象和生化功能，为使用 Pin1 进行药物设计提供了思路。两个模板肽序列已广泛用于 Pin1 的扩展或紧凑状态（Cdc25C，E-Q-P-L-pT-P-V-T-D-L；Pintide，W-F-Y-pS-P-R）。特定的 pSer/Thr-Pro 肽调节结构域间通讯以达到相反状态的方式尚不清楚。在这项研究中，我们将 8 种修饰肽的序列组成进行细分，并通过溶液核磁共振和分子动力学研究它们与 Pin1 的相互作用。证明了序列对 pSer-Pro 或 pThr-Pro 基序以及锚定 WW 结构域的不同残基的依赖性，Pin 肽（Pintide、PintideT、Pin25C 和 Pin25CT）将这种浓度积累传递到 PPIase 结构域，从而表现出两种锚定趋势。然而，Cdc 肽（Cdc25C、Cdc25CS、Cdctide 和 CdctideS）具有较低的结合能，使得构象难以达到稳定状态。此外，Pin1 受到紧凑和扩展状态的影响，序列以及苏氨酸或丝氨酸的精确调节。这些结果为 Pin1 通过 pSer/Thr-Pro 肽结合进行结构域间通讯提供了新的见解。
