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    Molecular Basis for p85 Dimerization and Allosteric Ligand Recognition

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    Name:
    PhD Dissertation_Aljedani-Arold2018.pdf
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    23.45Mb
    Format:
    PDF
    Description:
    Dissertation
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    Type
    Dissertation
    Authors
    Aljedani, Safia cc
    Advisors
    Arold, Stefan T. cc
    Committee members
    Bernado, Pau
    Hamdan, Samir cc
    Al-Babili, Salim cc
    Program
    Bioscience
    KAUST Department
    Biological and Environmental Sciences and Engineering (BESE) Division
    Date
    2018-12
    Embargo End Date
    2019-12-18
    Permanent link to this record
    http://hdl.handle.net/10754/630289
    
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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 became available to the public after the expiration of the embargo on 2019-12-18.
    Abstract
    The phosphatidylinositol-3-kinase α (PI3Kα) is a heterodimeric enzyme that is composed of a p85α regulatory subunit and a p110α catalytic subunit. PI3Kα plays a critical role in cell survival, growth and differentiation, and is the most frequently mutated pathway in human cancers. The PI3Kα pathway is also targeted by many viruses, such as the human immunodeficiency virus (HIV-1), the herpes simplex virus 1 (HSV-1) or the influenza A virus, to create favourable conditions for viral replication. The regulatory p85α stabilizes the catalytic p110α, but keeps it in an inhibited state. Various ligands can bind to p85α and allosterically activate p110α, but the mechanisms are still ill-defined. Intriguingly, p85α also binds to, and activates, the PTEN phosphatase, which is the antagonist of p110α. Previous studies indicated that only p85α monomers bind to the catalytic p110α subunit, whereas only p85α dimers bind to PTEN. These findings suggest that the balance of p85α monomers and dimers regulates the PI3Kα pathway, and that interrupting this equilibrium could lead to disease development. However, the molecular mechanism for p85α dimerization is controversial, and it is unknown why PTEN only binds to p85α dimers, whereas p110α only binds to p85α monomers. Here we set out to elucidate these questions, and to gain further understanding of how p85α ligands influence p85α dimerization and promote activation of p110α. We first established a comprehensive library of p85α fragments and protocols for their production and purification. By combining biophysical and structural methods such as small angle X-ray scattering, X-ray crystallography, nuclear magnetic resonance, microscale thermophoresis, and chemical crosslinking, we investigated the contributions of all p85α domains to dimerization and ligand binding. Contrarily to the prevailing thought in the field, we find that p85α dimerization and ligand recognition involves multiple domains, including those that directly bind to and inhibit p110α. This finding allows us to suggest a molecular mechanism that links p85α dimerization and allosteric p110α activation through ligands.
    Citation
    Aljedani, S. (2018). Molecular Basis for p85 Dimerization and Allosteric Ligand Recognition. KAUST Research Repository. https://doi.org/10.25781/KAUST-F1750
    DOI
    10.25781/KAUST-F1750
    ae974a485f413a2113503eed53cd6c53
    10.25781/KAUST-F1750
    Scopus Count
    Collections
    Biological and Environmental Sciences and Engineering (BESE) Division; Bioscience Program; Dissertations

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