| Titre : | IN SILICO ANALYSIS OF THE MUTATIONAL EFFECT ON TYK2 PROTEIN FUNCTION IN RELATION TO THE DIVERGENT AR-HIES CLINICAL PHENOTYPE | | Type de document : | thèse | | Auteurs : | ABBOU HANANE, Auteur | | Année de publication : | 2022 | | Langues : | Anglais (eng) | | Mots-clés : | AR-HIES TYK2 mutational effect prediction molecular docking AR-HIES, TYK2 prédiction de l'effet mutationnel amarrage moléculaire ES-AR TYK2 توقع تأثير الطفرات االلتحام الجزيئي. | | Résumé : | Autosomal Recessive Hyper IgE Syndrome is a primary immunodeficiency typified by
skin and sinopulmonary infections, eczema, and extremely high serum IgE. Complete loss of
function mutations of tyrosine Kinase 2 (TYK2) hinders signaling downstream of IL-6, IL-10,
IL-12, and IL-23, involved in the JAK-STAT signaling pathway, while the partial loss of
function alters the signaling of IL-23 specifically. We have predicted the mutational effect of
TYK2 mutations on the stability, flexibility, and function of each TYK2 domain, using
prediction tools and molecular docking. Our results have shown that deleterious mutations of
this kinase in the multiple domains alter the specific function of each one. Mutations in the
FERM domain altered the interactions between TYK2 and the box1 motif in the IL12RB1
receptor, mutations in the SH2 domain altered the interaction between the TYK2 and the box2
motif in the IL12RB1 receptor, mutations in the PSEUDOKINASE domain induced a
catalytically inactive TYK2, and mutations in the KINASE domain rigidified the protein,
preventing it from achieving its catalytic activity despite ATP binding. We have also
emphasized the partial loss of function aspect and how the mutational effect is contextdependent and residue-dependen | | Numéro (Thèse ou Mémoire) : | MM0022022 | | Président : | Azeddine Ibrahimi, | | Directeur : | . Ilham Kandoussi | | Juge : | Ouadghiri Mouna |
IN SILICO ANALYSIS OF THE MUTATIONAL EFFECT ON TYK2 PROTEIN FUNCTION IN RELATION TO THE DIVERGENT AR-HIES CLINICAL PHENOTYPE [thèse] / ABBOU HANANE, Auteur . - 2022. Langues : Anglais ( eng) | Mots-clés : | AR-HIES TYK2 mutational effect prediction molecular docking AR-HIES, TYK2 prédiction de l'effet mutationnel amarrage moléculaire ES-AR TYK2 توقع تأثير الطفرات االلتحام الجزيئي. | | Résumé : | Autosomal Recessive Hyper IgE Syndrome is a primary immunodeficiency typified by
skin and sinopulmonary infections, eczema, and extremely high serum IgE. Complete loss of
function mutations of tyrosine Kinase 2 (TYK2) hinders signaling downstream of IL-6, IL-10,
IL-12, and IL-23, involved in the JAK-STAT signaling pathway, while the partial loss of
function alters the signaling of IL-23 specifically. We have predicted the mutational effect of
TYK2 mutations on the stability, flexibility, and function of each TYK2 domain, using
prediction tools and molecular docking. Our results have shown that deleterious mutations of
this kinase in the multiple domains alter the specific function of each one. Mutations in the
FERM domain altered the interactions between TYK2 and the box1 motif in the IL12RB1
receptor, mutations in the SH2 domain altered the interaction between the TYK2 and the box2
motif in the IL12RB1 receptor, mutations in the PSEUDOKINASE domain induced a
catalytically inactive TYK2, and mutations in the KINASE domain rigidified the protein,
preventing it from achieving its catalytic activity despite ATP binding. We have also
emphasized the partial loss of function aspect and how the mutational effect is contextdependent and residue-dependen | | Numéro (Thèse ou Mémoire) : | MM0022022 | | Président : | Azeddine Ibrahimi, | | Directeur : | . Ilham Kandoussi | | Juge : | Ouadghiri Mouna |
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