Molecular Biomechanics, Heidelberg Institute for Theoretical Studies, 69118 Heidelberg, Germany.
Helsinki Institute of Life Science, Biomedicum Helsinki, University of Helsinki, 00290 Helsinki, Finland.
Proc Natl Acad Sci U S A. 2022 Mar 15;119(11):e2106098119. doi: 10.1073/pnas.2106098119. Epub 2022 Mar 8.
SignificanceThe pseudokinase integrin-linked kinase (ILK) is a central component of focal adhesions, cytoplasmic multiprotein complexes that integrate and transduce biochemical and mechanical signals from the extracellular environment into the cell and vice versa. However, the precise molecular functions, particularly the mechanosensory properties of ILK and the significance of retained adenosine triphosphate (ATP) binding, are still unclear. Combining molecular-dynamics simulations with cell biology, we establish a role for ATP binding to pseudokinases. We find that ATP promotes the structural stability of ILK, allosterically influences the interaction between ILK and its binding partner parvin at adhesions, and enhances the mechanoresistance of this complex. On the cellular level, ATP binding facilitates efficient traction force buildup, focal adhesion stabilization, and efficient cell migration.
意义
假激酶整合素连接激酶（ILK）是黏着斑的核心组成部分，黏着斑是细胞质多蛋白复合物，可将细胞外环境中的生化和机械信号整合并传递到细胞内，反之亦然。然而，ILK 的精确分子功能，特别是其机械敏感性，以及保留的三磷酸腺苷（ATP）结合的意义仍不清楚。我们将分子动力学模拟与细胞生物学相结合，确定了 ATP 结合到假激酶上的作用。我们发现，ATP 促进了 ILK 的结构稳定性，变构影响了 ILK 与其黏着斑结合伙伴 parvin 之间的相互作用，并增强了该复合物的抗机械性。在细胞水平上，ATP 结合促进了有效牵引力的形成、黏着斑的稳定以及细胞的高效迁移。
