Méthodes d’apprentissage et approches expérimentales appliqués aux réseaux d’interfaces protéiques

Abstract : The aim of this study is to understand protein assembly mechanisms. The assembly of a protein in an oligomer is particularly important because it is involved in many pathologies going from bacterial infection, Alzheimer like diseases or even some cancers. Protein assembly is the combination of two or more protein chains to induce a biological activity. The B subunit of the cholera toxin pentamer (CtxB5), which belongs to the family of AB5 toxins, is studied as the main model of assembly. Experimental results have provided information on the assembly of the toxin highlighting the involvement of certain amino acids. The first problem addressed in my thesis is to understand their role and see if network approaches are relevant to such investigation. I was able to show using amino acid mutations, that amino acids influence each other by cascade or "peer to peer" mechanisms in order to coordinate the various steps of the assembly (Chapters 4, 5 and 6). The structure and function of the proteins are defined by amino acid sequences which naturally vary due to genetic mutation. So I decided to expand this field of investigation to see if the cascade mechanism was generalized as a mean of disrupting a protein structure. Here it is to understand how a protein loses its function by way of a significant change of structure upon mutation. First, I studied dataset to know the characteristics of healthy protein networks (Chapter 7, 8 and 9), and after I looked at the effects of the systematic mutation of each amino acid of CtxB5 on its overall structure (Chapter 10 and 11). Mutations led from moderate to very large structural changes around the mutated amino acid or at long distances. These results are consistent with known effects of mutation: robustness (maintenance function), evolution or adaptation (emergence of a new feature) and fragility (pathologies). The results also show a weak correlation between the number of amino acid contacts of the mutated amino acid and the amount of structural change induced by its mutation. It is therefore not easy to anticipate the effect of a mutation: The last chapter of my thesis addresses this problem (Chapter 12).
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Mounia Achoch. Méthodes d’apprentissage et approches expérimentales appliqués aux réseaux d’interfaces protéiques. Bio-informatique [q-bio.QM]. Université Grenoble Alpes, 2015. Français. ⟨NNT : 2015GREAA022⟩. ⟨tel-01243262⟩

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