Etude des facteurs du démarrage de la traduction eIF5B et eIF3.

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Guillon, Laurent (2008) Etude des facteurs du démarrage de la traduction eIF5B et eIF3. Doctorat Biochimie, Laboratoire de Biochimie, EP/X p.209.

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Résumé

Le démarrage de la traduction est un processus central dans toute cellule. L’étude des protéines assistant le ribosome pour réaliser cette étape, les facteurs de démarrage (Initiation Factors Ifs), permet d’obtenir des informations sur les mécanismes moléculaires complexes assurant la fidélité et l’efficacité du démarrage.

La comparaison des jeux de facteurs protéiques dans les trois règnes du monde vivant a permis de mettre en évidence la présence de trois facteurs universellement conservés. Parmi ceux-ci, le facteur eucaryotique/archéen e/aIF5B, homologue au facteur bactérien IF2, stimule l’association des sous-unités ribosomales au même titre que chez les Bactéries. Néanmoins, l’universalité du facteur est limitée par l’absence d’interaction reportée entre le facteur e/aIF5B et l’ARNt initiateur alors que cette liaison est parfaitement caractérisée chez les Bactéries. Une partie de ce travail de thèse a permis d’étendre la similitude fonctionnelle entre les facteurs en mettant en évidence une liaison de l’ARNt initiateur méthionylé par le facteur e/aIF5B. Cette liaison présente des caractéristiques identiques à celle de l’ARNt initiateur méthionylé et formylé par le facteur bactérien IF2.

Une deuxième partie du travail de thèse a concerné le facteur eIF3, le plus complexe du système de démarrage chez les Eucaryotes. Ce complexe de 13 sous-unités chez l’humain et de 5 sous-unités chez la levure n’a pas d’équivalent dans les autres domaines du vivant bien qu’il joue un rôle central et essentiel chez les Eucaryotes. La compréhension de ses fonctions est néanmoins fortement limitée par le manque d’information à l’échelle moléculaire sur les interactions entre les sous-unités le composant et avec ses autres facteurs partenaires. De plus, le facteur s’avère être impliqué dans de nombreux cancers, ce qui étend l’intérêt de son étude. Mon travail a permis de développer une bibliothèque de vecteurs permettant de coexprimer les différentes sous-unités ou des formes stabilisées des sous-unités du facteur eIF3 de levure chez la Bactérie Escherichia coli. La purification des sous-unités isolées et de différents sous-complexes nous permet d’envisager la résolution de la structure du facteur et de son organisation par une approche alliant la cristallographie et la microscopie électronique.

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Table des Matières

Table des figures, Table des tableaux, Liste des abreviations

Chapitre I Introduction - 1

PARTIE A LE RIBOSOME, LE COEUR DE LA MACHINERIE DU DEMARRAGE - 5

I La biogénèse des ribosomes - 5

II Le coeur universellement conservé du ribosome - 7

III Différences entre ribosomes de diverses origines - 17

PARTIE B LE DEMARRAGE DE LA TRADUCTION - 22

I Le démarrage bactérien - 23

II Le démarrage chez les Eucaryotes - 26

III Le démarrage chez les Archées - 29

PARTIE C RELATIONS STRUCTURE/FONCTION DES FACTEURS DU DEMARRAGE EUCARYOTIQUE - 31

I Le complexe de prédémarrage 43S - 31

II Recrutement de l’ARNm au complexe de prédémarrage 43S et balayage de l’ARNm ... 39

III Sélection du codon de démarrage et réponse à l’appariement - 45

IV Régulation & modes alternatifs du démarrage de la traduction - 52

PARTIE D LE FACTEUR EIF3 - 58

I Composition d’eIF3 chez les Eucaryotes - 58

II Organisation du facteur eIF3 de S. cerevisiae - 60

III De l’organisation à la fonction - 63

IV Le rôle d’eIF3 dans la régulation de la traduction et le cancer - 67

CONCLUSION - 70

Chapitre II Le facteur e/aIF5B - 71

PARTIE A CLONAGE ET PURIFICATION DES FACTEURS DE DEMARRAGE E/AIF5B ET AIF1A - 73

I Clonage - 73

II Surproduction et purification - 74

PARTIE B PROTECTION DU MET-ARNT INITIATEUR PAR E/AIF5B - 75

I Le test de protection de la déacylation spontanée d’un ARNt aminoacylé - 75

II Résultats - 77

PARTIE C CRISTALLISATION DU FACTEUR - 83

I Obtention des cristaux - 83

II Diffraction - 84

DISCUSSION - 85

Chapitre III Le facteur eIF3 - 87

PARTIE A STRATEGIE DE PURIFICATION DU COMPLEXE EIF3 DE SACCHAROMYCES CEREVISIAE - 88

I Clonage des gènes codant pour les sous-unités du facteur eIF3 de levure - 89

II Essais de surproduction - 90

III Mise en place d’une stratégie de coexpression - 93

IV Clonages dans les vecteurs Duet et résultats préliminaires de la coexpression - 96

V Implémentations de la stratégie de purification - 101

VI Conclusion - 103

PARTIE B PURIFICATIONS DE DIFFERENTES FORMES DU FACTEUR EIF3 - 104

I Stratégie d’expression - 104

II Résultats des purifications - 105

III Conclusion - 110

PARTIE C LE COMPLEXE EIF3BC1-CC1-I-GC1, PREMIER PAS VERS LA RESOLUTION DE LA STRUCTURE DU FACTEUR EIF3 - 111

I Purification du complexe eIF3bC1-cC1-i-gC1 - 111

II Structure d’eIF3bC1-cC1-i-gC1 par microscopie électronique - 113

III Vers une structure du facteur eIF3 par microscopie électronique - 115

PARTIE D LES CRISTAUX D’EIF3I DE SACCHAROMYCES CERVISIAE : UN PROBLEME CRISTALLOGRAPHIQUE - 117

I Purification de la protéine - 117

II Principe de la cristallisation - 117

III Diffraction par les rayons X et acquisition des données - 119

DISCUSSION - 148

Chapitre IV Matériels et Méthodes - 149

I Techniques générales de biologie moléculaire, réactifs et tampons de purification - 150

II Etude du facteur e/aIF5B - 158

III Le facteur eIF3 - 161

IV La sous-unité eIF3i, cristallisation - 165

Annexes - 170

Références Bibliographiques - 188

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