8TEC

Crystal structure of Kindlin2 in complex with acylated beta1 integrin peptide

Summary for 8TEC

• Entry DOI: 10.2210/pdb8tec/pdb
• Related: 5xpy
• Descriptor: Fermitin family homolog 2, Integrin beta-1 (3 entities in total)
• Functional Keywords: kindlin, integrin, acylation, cell adhesion
• Biological source: Mus musculus (house mouse); More
• Total number of polymer chains: 3
• Total formula weight: 124217.32

Authors

Zhang, P.F.,Wu, J.H. (deposition date: 2023-07-06, release date: 2024-07-03, Last modification date: 2024-10-30)

Primary citation

Sidibe, A.,Mykuliak, V.V.,Zhang, P.,Hytonen, V.P.,Wu, J.,Wehrle-Haller, B.
Acetyl-NPKY of integrin-beta 1 binds KINDLIN2 to control endothelial cell proliferation and junctional integrity.
Iscience, 27:110129-110129, 2024

PubMed Abstract: 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.

PubMed: 38904068
DOI: 10.1016/j.isci.2024.110129

Experimental method

X-RAY DIFFRACTION (2.04 Å)