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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 (2022) Talin variant P229S compromises integrin activation and associates with multifaceted clinical symptoms. Human Molecular Genetics, 31 (24). pp. 4159-4172. ISSN 0964-6906. (doi:10.1093/hmg/ddac163) (KAR id:96115)

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https://doi.org/10.1093/hmg/ddac163

Abstract

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 characterisation 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.

Item Type: Article
DOI/Identification number: 10.1093/hmg/ddac163
Additional information: For the purpose of open access, the author(s) has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising.
Uncontrolled keywords: talin, variant, integrin, disease, cell adhesion, cell migration
Subjects: Q Science > QH Natural history > QH581.2 Cell Biology
Divisions: Divisions > Division of Natural Sciences > Biosciences
Funders: Biotechnology and Biological Sciences Research Council (https://ror.org/00cwqg982)
Academy of Finland (https://ror.org/05k73zm37)
Depositing User: Ben Goult
Date Deposited: 06 Aug 2022 21:20 UTC
Last Modified: 20 Nov 2023 15:40 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/96115 (The current URI for this page, for reference purposes)
Goult, Benjamin T: https://orcid.org/0000-0002-3438-2807
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