Universität zu Köln

Martin, Isabel M., Nava, Michele M., Wickstroem, Sara A. and Graeter, Frauke (2022). ATP allosterically stabilizes integrin-linked kinase for efficient force generation. Proc. Natl. Acad. Sci. U. S. A., 119 (11). WASHINGTON: NATL ACAD SCIENCES. ISSN 1091-6490

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Abstract

Focal adhesions link the actomyosin cytoskeleton to the extracellular matrix regulating cell adhesion, shape, and migration. Adhesions are dynamically assembled and disassembled in response to extrinsic and intrinsic forces, but how the essential adhesion component integrin-linked kinase (ILK) dynamically responds to mechanical force and what role adenosine triphosphate (ATP) bound to this pseudokinase plays remain elusive. Here, we apply force-probe molecular-dynamics simulations of human ILK:alpha-parvin coupled to traction force microscopy to explore ILK mechanotransducing functions. We identify two key salt-bridge-forming arginines within the allosteric, ATP-dependent force-propagation network of ILK. Disrupting this network by mutation impedes parvin binding, focal adhesion stabilization, force generation, and thus migration. Under tension, ATP shifts the balance from rupture of the complex to protein unfolding, indicating that ATP increases the force threshold required for focal adhesion disassembly. Our study proposes a role of ATP as an obligatory binding partner for structural and mechanical integrity of the pseudokinase ILK, ensuring efficient cellular force generation and migration.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Martin, Isabel M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Nava, Michele M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wickstroem, Sara A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Graeter, Frauke UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-685058
DOI:	10.1073/pnas.2106098119
Journal or Publication Title:	Proc. Natl. Acad. Sci. U. S. A.
Volume:	119
Number:	11
Date:	2022
Publisher:	NATL ACAD SCIENCES
Place of Publication:	WASHINGTON
ISSN:	1091-6490
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language STRUCTURAL BASIS; THERAPEUTIC TARGET; CELL-ADHESION; ALPHA-PARVIN; ILK; DOMAIN; PINCH; KINDLIN-2; BINDING; LOCALIZATION Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/68505