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    Mechanistic basis for calcium-sensing by the protein-tyrosine kinase 2-beta (PYK2)

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    Name:
    AfaqueAhmadMominThesis.pdf
    Size:
    15.23Mb
    Format:
    PDF
    Description:
    PhD Dissertation
    Embargo End Date:
    2021-09-30
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    Type
    Dissertation
    Authors
    Momin, Afaque Ahmad Imtiyaz cc
    Advisors
    Arold, Stefan T. cc
    Committee members
    Ladbury, John E.
    Gao, Xin cc
    Jaremko, Mariusz cc
    Program
    Bioscience
    KAUST Department
    Biological and Environmental Sciences and Engineering (BESE) Division
    Date
    2019-10
    Embargo End Date
    2021-09-30
    Permanent link to this record
    http://hdl.handle.net/10754/660323
    
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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 2021-09-30.
    Abstract
    The focal adhesion kinase (FAK) and the protein tyrosine kinase 2-beta (PYK2) are two closely related non-receptor tyrosine kinases that link cell adhesion, migration and proliferation, and thus also promote cancer cell invasiveness. FAK and PYK2 have the same domain structure (comprising the FERM, kinase and FAT domains) and possess several overlapping functions, however their cellular roles can be different or even opposing. In particular, PYK2 can be activated by calcium, and has important functions in the brain and neurodegenerative disease. The molecular basis for calcium-based activation of PYK2 is unclear and controversial. In this work we combined biophysical and structural methods to determine the molecular basis for calcium-sensing in PYK2. For this, we investigated the least-studied region of these kinases, namely the long linker (KFL) region between the kinase and FAT domains. This linker is only ~20% conserved between FAK and PYK2, and, therefore, is a prime candidate for causing their differential properties. We find that the linker harbors a helical segment, which is conserved in both FAK and PYK2, and contributes to their dimerization (an important step in their activation). Helix-flanking regions differ between both proteins, and we show that these of PYK2 create a non-canonical dimeric binding site for calcium-bound calmodulin. Calmodulin-binding is synergistic with linker dimerization in PYK2, explaining how calcium influx can be translated into activation of PYK2. Collectively, our work clarifies the capacities for FAK and PYK2 to receive, process and transduce cellular signals, and may provide new opportunities for targeted therapeutic intervention.
    Citation
    Momin, A. A. I. (2019). Mechanistic basis for calcium-sensing by the protein-tyrosine kinase 2-beta (PYK2). KAUST Research Repository. https://doi.org/10.25781/KAUST-58TJ7
    DOI
    10.25781/KAUST-58TJ7
    ae974a485f413a2113503eed53cd6c53
    10.25781/KAUST-58TJ7
    Scopus Count
    Collections
    Biological and Environmental Sciences and Engineering (BESE) Division; Bioscience Program; Dissertations

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