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On the benefit of bivalency in peptide Ligand/Pin1 interactions

机译：关于肽配体/ Pin1相互作用中双价的益处

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摘要

The human peptidyl prolyl cis/trans isomerase (PPIase) Pin1 has a key role in developmental processes and cell proliferation. Pin1 consists of an N-terminal WW domain and a C-terminal catalytic PPIase domain both targeted specifically to Ser(PO3H2)/Thr(PO3H2)-Pro sequences. Here, we report the enhanced affinity originating from bivalent binding of ligands toward Pin1 compared to monovalent binding. We developed composite peptides where an N-terminal segment represents a catalytic site-directed motif and a C-terminal segment exhibits a predominant affinity to the WW domain of Pin1 tethered by polyproline linkers of different chain length. We used NMR shift perturbation experiments to obtain information on the specific interaction of a bivalent ligand to both targeted sites of Pin1. The bivalent ligands allowed a considerable range of thermodynamic investigations using isothermal titration calorimetry and PPIase activity assays. They expressed up to 350-fold improved affinity toward Pin1 in the nanomolar range in comparison to the monovalent peptides. The distance between the two binding motifs was highly relevant for affinity. The optimum in affinity manifested by a linker length of five prolyl residues between active site- and WW domain-directed peptide fragments suggests that the corresponding domains in Pin1 are allowed to adopt preferred spatial arrangement upon ligand binding. (c) 2007 Elsevier Ltd. All rights reserved.
机译：人肽基脯氨酰顺/反异构酶（PPIase）Pin1在发育过程和细胞增殖中具有关键作用。 Pin1由N末端WW结构域和C末端催化PPIase结构域组成，两者均特异性靶向Ser（PO3H2）/ Thr（PO3H2）-Pro序列。在这里，我们报告与单价结合相比，增强的亲和力源自配体对Pin1的二价结合。我们开发了复合肽，其中N末端片段代表催化定点基序，而C末端片段对由不同链长的聚脯氨酸接头束缚的Pin1的WW域表现出主要的亲和力。我们使用NMR位移扰动实验来获得有关二价配体与Pin1的两个目标位点的特异性相互作用的信息。二价配体允许使用等温滴定量热法和PPIase活性测定进行大量的热力学研究。与单价肽相比，它们在纳摩尔范围内表达的对Pin1的亲和力提高了350倍。两个结合基序之间的距离与亲和力高度相关。活性位点和WW结构域定向的肽片段之间五个脯氨酰残基的连接子长度显示出最佳的亲和力，表明Pin1中的相应结构域在配体结合后可以采用优选的空间排列方式。 （c）2007 Elsevier Ltd.保留所有权利。

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