8tee
From Proteopedia
Crystal structure of Kindlin2 in complex with K794Q mutated beta1 integrin
Structural highlights
FunctionFERM2_MOUSE Scaffolding protein that enhances integrin activation mediated by TLN1 and/or TLN2, but activates integrins only weakly by itself. Binds to membranes enriched in phosphoinositides. Enhances integrin-mediated cell adhesion onto the extracellular matrix and cell spreading; this requires both its ability to interact with integrins and with phospholipid membranes. Required for the assembly of focal adhesions. Participates in the connection between extracellular matrix adhesion sites and the actin cytoskeleton and also in the orchestration of actin assembly and cell shape modulation. Recruits FBLIM1 to focal adhesions. Plays a role in the TGFB1 and integrin signaling pathways. Stabilizes active CTNNB1 and plays a role in the regulation of transcription mediated by CTNNB1 and TCF7L2/TCF4 and in Wnt signaling.[1] [2] [3] Publication Abstract from PubMedIntegrin-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-beta1 influences endothelial cell physiology and barrier function. Expression of an acetylation-mimetic beta1-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. beta1-K794Q-GFP induced constitutive MAPK signaling, junctional impairment, proliferation, and reduced contact inhibition at confluence. Structural analysis of Integrin-beta1 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-beta1. Thus, enhanced recruitment of KINDLIN2 to Lysine-acetylated Integrin-beta1 and resulting modulation of barrier function, offers new therapeutic possibilities for controlling vascular permeability and disease conditions. Acetyl-NPKY of integrin-beta1 binds KINDLIN2 to control endothelial cell proliferation and junctional integrity.,Sidibe A, Mykuliak VV, Zhang P, Hytonen VP, Wu J, Wehrle-Haller B iScience. 2024 May 28;27(6):110129. doi: 10.1016/j.isci.2024.110129. eCollection , 2024 Jun 21. PMID:38904068[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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