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Talin variant P229S compromises integrin activation and associates with multifaceted clinical symptoms

Adhesion of cells to the extracellular matrix (ECM) must be exquisitely coordinated to enable development and tissue homeostasis. Cell–ECM interactions are regulated by multiple signalling pathways that coordinate the activation state of the integrin family of ECM receptors. The protein talin is piv...

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Autores principales: Azizi, Latifeh, Varela, Lorena, Turkki, Paula, Mykuliak, Vasyl V, Korpela, Sanna, Ihalainen, Teemu O, Church, Joseph, Hytönen, Vesa P, Goult, Benjamin T
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9759328/
https://www.ncbi.nlm.nih.gov/pubmed/35861643
http://dx.doi.org/10.1093/hmg/ddac163
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author Azizi, Latifeh
Varela, Lorena
Turkki, Paula
Mykuliak, Vasyl V
Korpela, Sanna
Ihalainen, Teemu O
Church, Joseph
Hytönen, Vesa P
Goult, Benjamin T
author_facet Azizi, Latifeh
Varela, Lorena
Turkki, Paula
Mykuliak, Vasyl V
Korpela, Sanna
Ihalainen, Teemu O
Church, Joseph
Hytönen, Vesa P
Goult, Benjamin T
author_sort Azizi, Latifeh
collection PubMed
description Adhesion of cells to the extracellular matrix (ECM) must be exquisitely coordinated to enable development and tissue homeostasis. Cell–ECM interactions are regulated by multiple signalling pathways that coordinate the activation state of the integrin family of ECM receptors. The protein talin is pivotal in this process, and talin’s simultaneous interactions with the cytoplasmic tails of the integrins and the plasma membrane are essential to enable robust, dynamic control of integrin activation and cell–ECM adhesion. Here, we report the identification of a de novo heterozygous c.685C>T (p.Pro229Ser) variant in the TLN1 gene from a patient with a complex phenotype. The mutation is located in the talin head region at the interface between the F2 and F3 domains. The characterization of this novel p.P229S talin variant reveals the disruption of adhesion dynamics that result from disturbance of the F2–F3 domain interface in the talin head. Using biophysical, computational and cell biological techniques, we find that the variant perturbs the synergy between the integrin-binding F3 and the membrane-binding F2 domains, compromising integrin activation, adhesion and cell migration. Whilst this remains a variant of uncertain significance, it is probable that the dysregulation of adhesion dynamics we observe in cells contributes to the multifaceted clinical symptoms of the patient and may provide insight into the multitude of cellular processes dependent on talin-mediated adhesion dynamics.
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spelling pubmed-97593282022-12-19 Talin variant P229S compromises integrin activation and associates with multifaceted clinical symptoms Azizi, Latifeh Varela, Lorena Turkki, Paula Mykuliak, Vasyl V Korpela, Sanna Ihalainen, Teemu O Church, Joseph Hytönen, Vesa P Goult, Benjamin T Hum Mol Genet Original Article Adhesion of cells to the extracellular matrix (ECM) must be exquisitely coordinated to enable development and tissue homeostasis. Cell–ECM interactions are regulated by multiple signalling pathways that coordinate the activation state of the integrin family of ECM receptors. The protein talin is pivotal in this process, and talin’s simultaneous interactions with the cytoplasmic tails of the integrins and the plasma membrane are essential to enable robust, dynamic control of integrin activation and cell–ECM adhesion. Here, we report the identification of a de novo heterozygous c.685C>T (p.Pro229Ser) variant in the TLN1 gene from a patient with a complex phenotype. The mutation is located in the talin head region at the interface between the F2 and F3 domains. The characterization of this novel p.P229S talin variant reveals the disruption of adhesion dynamics that result from disturbance of the F2–F3 domain interface in the talin head. Using biophysical, computational and cell biological techniques, we find that the variant perturbs the synergy between the integrin-binding F3 and the membrane-binding F2 domains, compromising integrin activation, adhesion and cell migration. Whilst this remains a variant of uncertain significance, it is probable that the dysregulation of adhesion dynamics we observe in cells contributes to the multifaceted clinical symptoms of the patient and may provide insight into the multitude of cellular processes dependent on talin-mediated adhesion dynamics. Oxford University Press 2022-07-21 /pmc/articles/PMC9759328/ /pubmed/35861643 http://dx.doi.org/10.1093/hmg/ddac163 Text en © The Author(s) 2022. Published by Oxford University Press. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Article
Azizi, Latifeh
Varela, Lorena
Turkki, Paula
Mykuliak, Vasyl V
Korpela, Sanna
Ihalainen, Teemu O
Church, Joseph
Hytönen, Vesa P
Goult, Benjamin T
Talin variant P229S compromises integrin activation and associates with multifaceted clinical symptoms
title Talin variant P229S compromises integrin activation and associates with multifaceted clinical symptoms
title_full Talin variant P229S compromises integrin activation and associates with multifaceted clinical symptoms
title_fullStr Talin variant P229S compromises integrin activation and associates with multifaceted clinical symptoms
title_full_unstemmed Talin variant P229S compromises integrin activation and associates with multifaceted clinical symptoms
title_short Talin variant P229S compromises integrin activation and associates with multifaceted clinical symptoms
title_sort talin variant p229s compromises integrin activation and associates with multifaceted clinical symptoms
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9759328/
https://www.ncbi.nlm.nih.gov/pubmed/35861643
http://dx.doi.org/10.1093/hmg/ddac163
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