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Université Du Québec À Montréal UNIVERSITÉ DU QUÉBEC À MONTRÉAL CONVERSION CONFORMATIONNELLE SECONDAIRE ET QUATERNAIRE D'HORMONES PEPTIDIQUES: ÉQUILIBRE ENTRE FONCTION BIOLOGIQUE ET AUTO-ASSEMBLAGE PATHOLOGIQUE THÈSE PRÉSENTÉE COMME EXIGENCE PARTIELLE DU DOCTORAT EN BIOCHIMIE PAR NOÉ QUITTOT SEPTEMBRE 2020 UNIVERSITÉ DU QUÉBEC À MONTRÉAL Service des bibliothèques Avertissement La diffusion de cette thèse se fait dans le respect des droits de son auteur, qui a signé le formulaire Autorisation de reproduire et de diffuser un travail de recherche de cycles supérieurs (SDU-522 – Rév.10-2015). Cette autorisation stipule que «conformément à l’article 11 du Règlement no 8 des études de cycles supérieurs, [l’auteur] concède à l’Université du Québec à Montréal une licence non exclusive d’utilisation et de publication de la totalité ou d’une partie importante de [son] travail de recherche pour des fins pédagogiques et non commerciales. Plus précisément, [l’auteur] autorise l’Université du Québec à Montréal à reproduire, diffuser, prêter, distribuer ou vendre des copies de [son] travail de recherche à des fins non commerciales sur quelque support que ce soit, y compris l’Internet. Cette licence et cette autorisation n’entraînent pas une renonciation de [la] part [de l’auteur] à [ses] droits moraux ni à [ses] droits de propriété intellectuelle. Sauf entente contraire, [l’auteur] conserve la liberté de diffuser et de commercialiser ou non ce travail dont [il] possède un exemplaire.» REMERCIEMENTS Au Professeur Steve Bourgault, à qui je souhaite tout d’abord exprimer ma gratitude pour m’avoir accepté en tant qu’étudiant au doctorat au sein de son laboratoire. Merci d’avoir été un directeur de thèse présent et à l’écoute tout au long de mon doctorat. À Steve, merci de ta bienveillance à mon égard et à celle de ma famille. Merci également, quoi qu’on puisse en dire, de ta patience! À mes parents, que j’ai su peu rassurés à mon départ, je vous remercie de m’avoir fait confiance et surtout de me soutenir depuis le début. Je remercie aussi mes frères qui sont toujours une source d’inspiration, Lydia et mes grands-parents pour leur soutien. Je voudrais remercier chaleureusement mes brillants collègues auprès desquel.les j’ai pu tant apprendre et dont je garde d’excellents souvenirs. Merci à Carole-Anne, Trang, Armelle, Mathieu, Margaryta, Billel, Mathew, Ximena, Guillaume, Soultan, Élizabeth, Mathilde, Nadjib, Mélanie, Barbara et Alexandre. Je souhaite également remercier mes ami.es en France pour m’avoir soutenu malgré la distance. Enfin, à Dishani, à qui je pense pouvoir adresser mille merci pour tout, tous les jours, et à toi mon petit Léo d’être là. À nous trois, la suite promet d’être belle. TABLE DES MATIÈRES LISTE DES FIGURES .............................................................................................. viii LISTE DES TABLEAUX ........................................................................................... xi LISTE DES ABRÉVIATIONS, SIGLES ET ACRONYMES ................................. xii RÉSUMÉ ................................................................................................................. xvi CHAPITRE I: INTRODUCTION .............................................................................. 1 1.1 Ligands peptidiques des récepteurs couplés aux protéines G de la classe B ........ 1 1.1.1 Membres et structure primaire ............................................................... 1 1.1.2 Récepteurs couplés aux protéines G de la classe B ................................ 4 1.1.3 Fonctions biologiques des RCPG de la classe B .................................... 7 1.1.4 Structure secondaire des ligands peptidiques ....................................... 10 1.1.5 Auto-assemblage et structure quaternaire des ligands peptidiques ........................................................................................... 11 1.2 Amyloïdes ........................................................................................................... 12 1.2.1 Amyloïdes fonctionnels ........................................................................ 13 1.2.2 Amyloïdes pathologiques ..................................................................... 16 1.2.3 Organisation supramoléculaire des assemblages amyloïdes ................ 18 1.2.4 Mécanisme d’auto-assemblage des polypeptides amyloïdogéniques ................................................................................. 21 1.3 Diabète de type II et dépôts amyloïdes ............................................................... 23 1.3.1 Caractéristiques du diabète de type II .................................................. 23 1.3.2 Dépôts amyloïdes pancréatiques .......................................................... 24 1.4 Islet amyloid polypeptide .................................................................................... 25 1.4.1 Expression, maturation et entreposage de l’IAPP ................................ 25 1.4.2 Phylogénie de l’IAPP ........................................................................... 27 1.4.3 Structure secondaire de l’IAPP ............................................................ 29 iv 1.4.4 Activités biologiques et rôle pathologique de l’IAPP .......................... 31 1.4.5 Structure des fibres amyloïdes d’IAPP ................................................ 32 1.4.6 Mécanismes d’auto-assemblage de l’IAPP .......................................... 35 1.4.7 Cytotoxicité de l’IAPP ......................................................................... 36 1.4.7.1 Espèces cytotoxiques de l’IAPP ............................................ 36 1.4.7.2 Mécanismes de cytotoxicité de l’IAPP .................................. 38 1.4.8 Rôle des glycosaminoglycanes dans l’auto-assemblage et la cytotoxicité de l’IAPP .................................................................. 41 1.4.9 Inhibiteurs de la formation des fibres amyloïdes ................................. 43 1.5 Sécrétine .............................................................................................................. 45 1.5.1 Activités biologiques de la sécrétine ..................................................... 45 1.5.2 Modèle de la catalyse membranaire ...................................................... 47 1.6 Glycosaminoglycanes .......................................................................................... 49 1.7 Problématique et hypothèse ................................................................................ 51 1.8 Objectifs .............................................................................................................. 53 CHAPITRE II: ARTICLE I: KINETIC AND CONFORMATIONAL INSIGHTS INTO ISLET AMYLOID POLYPEPTIDE SELF-ASSEMBLY USING A BIARSENICAL FLUOROGENIC PROBE ............................................ 54 Contributions des auteurs .......................................................................................... 55 2.1 Résumé ................................................................................................................ 56 2.2 Abstract ............................................................................................................... 57 2.3 Introduction ......................................................................................................... 58 2.4 Experimental section ........................................................................................... 61 2.4.1 Peptides Synthesis ................................................................................ 61 2.4.2 IAPP Sample Preparation ..................................................................... 61 2.4.3 Fluorescence Measurement .................................................................. 62 2.4.4 Circular Dichroism Spectroscopy ........................................................ 62 2.4.5 Dynamic light scattering ...................................................................... 63 2.4.6 Atomic force microscopy ..................................................................... 63 2.4.7 Transmission Electron Microscopy ...................................................... 64 2.4.8 Preparation of Large Unilamellar Vesicles .......................................... 64 v 2.4.9 Kinetics of Self-Assembly ................................................................... 64 2.4.10 Photochemical-Induced Cross-Linking (PICUP) ............................... 65 2.5 Results and discussion ........................................................................................ 66 2.5.1 FlAsH detects IAPP amyloid fibrils but not prefibrillar species .......... 66 2.5.2 Kinetics of IAPP self-assembly with FlAsH detection ........................ 70 2.5.3 Cys-Cys motif at the C-terminus allows FlAsH detection of prefibrillar species ............................................................................ 74 2.5.4 IAPP oligomerization can be monitored by introducing a Cys-Cys motif at the C-terminus ....................................................... 78 2.5.5 Stability of the tetra-Cys motif within prefibrillar species ................... 81 2.5.6 FlAsH detection of oligomers assembled from the non-amyloidogenic rodent IAPP .................................................... 83 2.5.7 Detection of ThT-negative amyloid fibrils with FlAsH ....................... 86 2.5.8 Monitoring self-assembly with FlAsH detection in presence of biological co-factors and inhibitors ............................... 88 2.6 Conclusion ..........................................................................................................
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