Cargando…

ATP allosterically stabilizes integrin-linked kinase for efficient force generation

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) dynam...

Descripción completa

Detalles Bibliográficos
Autores principales: Martin, Isabel M., Nava, Michele M., Wickström, Sara A., Gräter, Frauke
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8933812/
https://www.ncbi.nlm.nih.gov/pubmed/35259013
http://dx.doi.org/10.1073/pnas.2106098119
_version_ 1784671739228192768
author Martin, Isabel M.
Nava, Michele M.
Wickström, Sara A.
Gräter, Frauke
author_facet Martin, Isabel M.
Nava, Michele M.
Wickström, Sara A.
Gräter, Frauke
author_sort Martin, Isabel M.
collection PubMed
description 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:α-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.
format Online
Article
Text
id pubmed-8933812
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher National Academy of Sciences
record_format MEDLINE/PubMed
spelling pubmed-89338122022-03-20 ATP allosterically stabilizes integrin-linked kinase for efficient force generation Martin, Isabel M. Nava, Michele M. Wickström, Sara A. Gräter, Frauke Proc Natl Acad Sci U S A Physical Sciences 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:α-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. National Academy of Sciences 2022-03-08 2022-03-15 /pmc/articles/PMC8933812/ /pubmed/35259013 http://dx.doi.org/10.1073/pnas.2106098119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Physical Sciences
Martin, Isabel M.
Nava, Michele M.
Wickström, Sara A.
Gräter, Frauke
ATP allosterically stabilizes integrin-linked kinase for efficient force generation
title ATP allosterically stabilizes integrin-linked kinase for efficient force generation
title_full ATP allosterically stabilizes integrin-linked kinase for efficient force generation
title_fullStr ATP allosterically stabilizes integrin-linked kinase for efficient force generation
title_full_unstemmed ATP allosterically stabilizes integrin-linked kinase for efficient force generation
title_short ATP allosterically stabilizes integrin-linked kinase for efficient force generation
title_sort atp allosterically stabilizes integrin-linked kinase for efficient force generation
topic Physical Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8933812/
https://www.ncbi.nlm.nih.gov/pubmed/35259013
http://dx.doi.org/10.1073/pnas.2106098119
work_keys_str_mv AT martinisabelm atpallostericallystabilizesintegrinlinkedkinaseforefficientforcegeneration
AT navamichelem atpallostericallystabilizesintegrinlinkedkinaseforefficientforcegeneration
AT wickstromsaraa atpallostericallystabilizesintegrinlinkedkinaseforefficientforcegeneration
AT graterfrauke atpallostericallystabilizesintegrinlinkedkinaseforefficientforcegeneration