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

Latifeh Azizi, Lorena Varela, Paula Turkki, Vasyl V Mykuliak, Sanna Korpela, Teemu O Ihalainen, Joseph Church, Vesa P Hytönen, Benjamin T Goult

Tutkimustuotos: ArtikkeliScientificvertaisarvioitu

2 Sitaatiot (Scopus)
11 Lataukset (Pure)

Abstrakti

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.
AlkuperäiskieliEnglanti
Sivut4159-4172
Sivumäärä14
JulkaisuHUMAN MOLECULAR GENETICS
Vuosikerta31
Numero24
DOI - pysyväislinkit
TilaJulkaistu - 15 jouluk. 2022
OKM-julkaisutyyppiA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä

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