Acetyl-NPKY of integrin-β1 binds KINDLIN2 to control endothelial cell proliferation and junctional integrity

• Published in: iScience Vol. 27; no. 6; p. 110129
• Main Authors: Sidibé, Adama, Mykuliak, Vasyl V., Zhang, Pingfeng, Hytönen, Vesa P., Wu, Jinhua, Wehrle-Haller, Bernhard
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.06.2024; Elsevier
• Subjects: Cell; Cell biology; Structural biology; Cell biology; Cell; Structural biology
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2024.110129

Integrin-dependent crosstalk between cell-matrix adhesions and cell-cell junctions is critical for controlling endothelial permeability and proliferation in cancer and inflammatory diseases but remains poorly understood. Here, we investigated how acetylation of the distal NPKY-motif of Integrin-β1 influences endothelial cell physiology and barrier function. Expression of an acetylation-mimetic β1-K794Q-GFP mutant led to the accumulation of immature cell-matrix adhesions accompanied by a transcriptomic reprograming of endothelial cells, involving genes associated with cell adhesion, proliferation, polarity, and barrier function. β1-K794Q-GFP induced constitutive MAPK signaling, junctional impairment, proliferation, and reduced contact inhibition at confluence. Structural analysis of Integrin-β1 interaction with KINDLIN2, biochemical pulldown assay, and binding energy determination by using molecular dynamics simulation showed that acetylation of K794 and the K794Q-mutant increased KINDLIN2 binding affinity to the Integrin-β1. Thus, enhanced recruitment of KINDLIN2 to Lysine-acetylated Integrin-β1 and resulting modulation of barrier function, offers new therapeutic possibilities for controlling vascular permeability and disease conditions. [Display omitted] •Crystal structures of acetylated and K794Q-mutated Integrin-β1 with KINDLIN2•β1-K794Q induces KINDLIN2 binding and immature adhesions in endothelial cells•β1-K794Q induces a transcriptomic change of junctional and proliferation genes•β1-K794Q impairs endothelial barrier function and contact inhibition of proliferation Cell biology; Cell; Structural biology