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Structural Mass Spectrometry Analysis of RNA Chaperones and Protein Therapeutics

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dc.contributor.advisorWilson, Derek J.
dc.contributor.authorBrown, Kerene Andrea
dc.date.accessioned2020-08-11T12:39:25Z
dc.date.available2020-08-11T12:39:25Z
dc.date.copyright2020-01
dc.date.issued2020-08-11
dc.date.updated2020-08-11T12:39:25Z
dc.degree.disciplineChemistry
dc.degree.levelDoctoral
dc.degree.namePhD - Doctor of Philosophy
dc.description.abstractSince the advent of soft ionization techniques, most notably electrospray ionization (ESI), the application of mass spectrometry (MS) analysis has expanded to intact biomolecules. ESI-MS gave rise to the field of structural MS (a relatively new tool in structural biology) which involves different types of MS techniques such as: Native, Ion Mobility, chemical labelling and proteomics. Conventional techniques such as Nuclear Magnetic Resonance (NMR) and X-ray crystallography provide high resolution structures of proteins. Although MS cannot provide the same level of resolution, it provides important structural information such as: binding stoichiometry, mass, size, subunit composition, ligand binding sites, stability, amino acid sequence and post-translational modifications (PTMs). In this work, structural MS was employed as a tool in the characterization of a crucial RNA chaperone, human La (hLa) protein, that is implicated in the processing of various types of cellular and viral RNAs. Many RNA chaperones such as hLa have large unstructured regions which make them difficult to study on a structural basis. Work done here revealed that the C-terminal domain (CTD) of hLa plays a role in binding RNA and that it binds structured and unstructured RNA using distinct dynamic modes. In addition, work was done to support a previous hypothesis about the presence of an interdomain interaction in hLa that affects nuclear trafficking and RNA binding. Additionally, the same structural MS techniques were used to assess the biosimilarity between a biological drug, Avastin, and its biosimilar in pre-clinical development. Work was done to test the structural similarity between the two drugs and the batch-to-batch variability of the biosimilar. Structural MS proved to be an effective technique in the rapid and facile characterization of biosimilarity and in the analysis of RNA binding activity of RNA chaperones.
dc.identifier.urihttp://hdl.handle.net/10315/37697
dc.languageen
dc.rightsAuthor owns copyright, except where explicitly noted. Please contact the author directly with licensing requests.
dc.subjectAnalytical chemistry
dc.subject.keywordsMass Spectrometry
dc.subject.keywordsProtein
dc.subject.keywordsHydrogen Deuterium Exchange
dc.subject.keywordsRNA
dc.subject.keywordsAntibody
dc.subject.keywordsBiosimilar
dc.subject.keywordsBiologics
dc.subject.keywordsLa protein
dc.subject.keywordsAvastin
dc.subject.keywordsBevacizumab
dc.subject.keywordsIon Mobility
dc.subject.keywordsRNA Chaperones
dc.subject.keywordsCollision Induced Unfolding
dc.subject.keywordsRNA Binding Protein
dc.titleStructural Mass Spectrometry Analysis of RNA Chaperones and Protein Therapeutics
dc.typeElectronic Thesis or Dissertation

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