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Title: Evolutionary, structural and functional features of cellular signalling networks
Author: Lang, Benjamin
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2013
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The post-translational modification of proteins is a fundamental means of biological information processing, with important functions in development, homeostasis and disease. Post-translational modifications (PTMs) can dynamically diversify the proteome in response to intracellular and extracellular signals. Since thousands of modified residues as well as entirely new modification types have recently been discovered in proteins, elucidating their biological functions and identifying the protein components of these PTM systems is a fundamental problem. Chapter 1 gives an overview of the types and known biological functions of different PTMs, as well as experimental methods used to detect them. Intrinsic disorder in proteins is introduced as a structural feature which may influence local evolutionary rates. Several examples of complex PTM signalling systems are then described. Chapter 2 presents a study of the evolution of modified amino acids in human proteins. By analysing sequence, polymorphism and mutation data at the species, population and individual levels, we observed significant evolutionary constraints on all PTM types for which extensive data was available, as well as overrepresentation of amino acids which mimic modified residues at equivalent positions. Chapter 3 applies a framework for the identification of important components of PTM signalling systems to lysine acetylation. The proteins of this system were found to be similarly conserved as essential genes. Their evolutionary histories suggested a conserved origin in chromatin regulation, followed by functional diversification. Chapter 4 extends the scope to signalling via transcriptional regulation, and presents a comprehensive overview of the interactome of the stem cell transcription factor Oct4. The results presented here facilitated characterisation of a novel post-translational modifier of Oct4, the glycosyltransferase Ogt. Chapter 5 highlights my key findings from applying evolutionary and data integration approaches to signalling networks, and outlines their implications for the study of novel signalling systems and for their engineering in synthetic biology. This dissertation therefore illuminates evolutionary, structural and functional principles of cellular signalling networks across species and within populations.
Supervisor: Mohan, Madan Babu Sponsor: Herchel Smith Research Studentship
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: Systems Biology ; Cell Signalling ; Networks ; Evolution ; Post-translational modifications ; PTMs ; Phosphorylation ; Acetylation ; Methylation ; Glycosylation ; N-linked glycosylation ; Intrinsically disordered proteins ; Unstructured proteins ; Non-globular proteins ; Evolutionary rates ; Human variation ; Human disease ; Oct4 ; Stem cells ; Interactome ; Lysine acetylation ; Modified amino acids ; Data integration ; Computational Biology ; Evolutionary pressure ; Sequence conservation ; Sequence evolution ; Evolutionary conservation ; Glycosyltransferase