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    The Role of the FAT Domain in Controlling Localization and Activation of the Focal Adhesion Kinase (FAK)

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    Name:
    RayanNaserThesis.pdf
    Size:
    5.701Mb
    Format:
    PDF
    Description:
    PhD Dissertation
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    Type
    Dissertation
    Authors
    Naser, Rayan Mohammad Mahmoud cc
    Advisors
    Arold, Stefan T. cc
    Committee members
    Aranda, Manuel cc
    Jaremko, Lukasz
    Watts, Anthony
    Program
    Bioscience
    KAUST Department
    Biological and Environmental Sciences and Engineering (BESE) Division
    Date
    2019-11
    Embargo End Date
    2020-11-28
    Permanent link to this record
    http://hdl.handle.net/10754/660326
    
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    Access Restrictions
    At the time of archiving, the student author of this dissertation opted to temporarily restrict access to it. The full text of this dissertation will become available to the public after the expiration of the embargo on 2020-11-28.
    Abstract
    Focal adhesion kinase (FAK) controls the assembly of focal adhesion sites and transduces signals from several membrane receptors. Controlled activation and localization of FAK functionally links cell adhesion, migration and survival. FAK is overexpressed in many cancer types, promoting tumor invasiveness and metastasis. The molecular mechanisms allowing FAK to fulfil numerous different functions and act as versatile ‘nanomachines’ are poorly understood. We have previously revealed that ligand-induced dimerization along with intramolecular interactions control FAK activation and localization where the C-terminal focal adhesion targeting (FAT) domain is strictly involved. In this study, we combine NMR with X-ray crystallography, as well as biophysical and computational methods to understand the molecular mechanisms that link the large-scale dynamics and intramolecular and intermolecular interactions of FAT into FAK’s capacity to integrate various stimuli into a site-specific function. Our results reveal FAT-mediated dynamical interplays between binding of known and newly discovered FAT ligands, and multimerization and autoactivation of FAK. Additionally, we investigate the impact of neuronal alternative splicing on FAT dynamics and interactions. Collectively, our results elucidate FAT’s role in allosterically controlling various FAK functions, and might inspire allosteric protein-protein interaction inhibitors against FAK-dependent cancer cell proliferation.
    Citation
    Naser, R. M. M. (2019). The Role of the FAT Domain in Controlling Localization and Activation of the Focal Adhesion Kinase (FAK). KAUST Research Repository. https://doi.org/10.25781/KAUST-6QLA1
    DOI
    10.25781/KAUST-6QLA1
    ae974a485f413a2113503eed53cd6c53
    10.25781/KAUST-6QLA1
    Scopus Count
    Collections
    Biological and Environmental Sciences and Engineering (BESE) Division; Bioscience Program; Dissertations

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