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桩蛋白与粘着斑靶向结构域的构象动力学及多模态相互作用

Conformational dynamics and multimodal interaction of Paxillin with the focal adhesion targeting domain.

作者信息

Bhattacharya Supriyo, He Yanan, Chen Yihong, Mohanty Atish, Grishaev Alexander, Kulkarni Prakash, Salgia Ravi, Orban John

机构信息

Department of Computational and Quantitative Medicine, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010-3000, USA.

University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, MD 20850, USA.

出版信息

Sci Adv. 2025 Jun 20;11(25):eadt9936. doi: 10.1126/sciadv.adt9936. Epub 2025 Jun 18.

Abstract

Paxillin (PXN) and focal adhesion kinase (FAK) are two major components of the focal adhesion complex, a multiprotein structure linking the intracellular cytoskeleton to the cell exterior. The interaction between the disordered amino-terminal domain of PXN and the carboxyl-terminal targeting domain of FAK (FAT) is necessary and sufficient for localizing FAK to focal adhesions. Furthermore, PXN serves as a platform for recruiting other proteins that together control the dynamic changes needed for cell migration and survival. Here, we show that the PXN N-domain undergoes significant compaction upon FAT binding, forming a 48-kilodalton multimodal complex with four major interconverting states. Although the complex is flexible, each state has unique sets of contacts involving disordered regions that are both highly represented in ensembles and conserved. PXN being a hub protein, the results provide a structural basis for understanding how shifts in the multistate equilibrium (e.g., through ligand binding and phosphorylation) may rewire cellular networks leading to phenotypic changes.

摘要

桩蛋白(PXN)和粘着斑激酶(FAK)是粘着斑复合体的两个主要组成部分,粘着斑复合体是一种将细胞内细胞骨架与细胞外部连接起来的多蛋白结构。PXN无序的氨基末端结构域与FAK的羧基末端靶向结构域(FAT)之间的相互作用对于将FAK定位到粘着斑是必要且充分的。此外,PXN作为一个平台,用于招募其他共同控制细胞迁移和存活所需动态变化的蛋白质。在这里,我们表明PXN的N结构域在与FAT结合后会发生显著的压缩,形成一个具有四种主要相互转化状态的48千道尔顿多模态复合体。尽管该复合体具有灵活性,但每种状态都有独特的接触集,涉及在集合中高度代表且保守的无序区域。由于PXN是一种枢纽蛋白,这些结果为理解多状态平衡的转变(例如通过配体结合和磷酸化)如何重新连接细胞网络导致表型变化提供了结构基础。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4308/12175908/43bfcff9f058/sciadv.adt9936-f1.jpg

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