Structure-function of Talin1: An integrin adaptor protein involved in health and disease

    Tutkimustuotos: VäitöskirjaCollection of Articles

    Abstrakti

    A cell is the smallest structural and functional unit of an organism. Cells dynamically interact with their surrounding environment. The substance filling the space between cells is a network of proteins and polysaccharides and is called extracellular matrix the (ECM). Cell surface receptors play a vital role in mediating cell-ECM and other interactions. Integrins are cell surface receptors participating in a wide range of biological processes including cell adhesion, homeostasis, immune responses, and cancer. One of the most important aspects of integrins is the bidirectional signalling across the plasma membrane. Coordinated interaction between ECM, receptors and cytoskeleton is essential in the cell adhesion process. Talin is a cytoplasmic protein that binds directly to integrin β-subunits, regulating integrin signalling and connecting them with the actin cytoskeleton. In healthy cells, when talin undergoes force-induced mechanical unfolding, new recognition sites are exposed for binding to cytoskeletal proteins that are involved in mechanotransduction. Dysregulation of talin or its activators may lead to diseased state, deviating integrin activation and mechanotransduction. Furthermore, such disorder may cause changes in cell migration, spreading and overall survival. In publications I and II, we have focused on the structure and function of the talin head domain using molecular dynamic simulations, cell biology and biochemical analyses. We found that a flexible loop in the talin head subdomain F1 is important for β3-integrin clustering. In addition, we found that the C-terminal poly-lysine motif in the talin head mediates FERM interdomain contacts, assuring the FERM-folded configuration of the talin head. In publications III and IV, disease-associated talin point mutations were investigated. We found that even small changes in talin can lead to dramatic effects on cell function. In publication III, we developed a bioinformatic pipeline and scoring system to analyse talin1 point mutations that were found to be associated with cancer in previous studies. An I392N point mutation in the F3 domain increased cell migration and invasion but decreased integrin β1 activation. An L2509P point mutation in the dimerization domain led to a non-polarised cellular phenotype and disruption of adhesion maturation due to a lack of dimerisation and actin binding of the talin´s mutant. Publication IV discusses the identification of a de novo heterozygous variant P229S found from a patient with complex phenotype. This mutation led to local alterations of the F2-F3 domain interface compromising integrin activation, adhesion composition and cell migration. Furthermore, point mutations found from spontaneous coronary artery dissection (SCAD) patients were investigated (unpublished data), adding considerable supportive data demonstrating the impact of talin point mutations on cell function. Our findings suggest that disease associated point mutations in talin1 can affect cell behaviour and may contribute to the progression of different diseases. In addition, the importance of proper connections between integrins and the actin cytoskeleton through talin1 is a critical factor for cell´s health.
    AlkuperäiskieliEnglanti
    JulkaisupaikkaTampere
    ISBN (elektroninen)978-952-03-2984-6
    TilaJulkaistu - 2023
    OKM-julkaisutyyppiG5 Artikkeliväitöskirja

    Julkaisusarja

    NimiTampere University Dissertations - Tampereen yliopiston väitöskirjat
    Vuosikerta832
    ISSN (painettu)2489-9860
    ISSN (elektroninen)2490-0028

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