Mechanisms of OGT-mediated HCF-1 protein maturation

Détails

Ressource 1Télécharger: BIB_37447C135825.P001.pdf (18345.29 [Ko])
Etat: Serval
Version: Après imprimatur
ID Serval
serval:BIB_37447C135825
Type
Thèse: thèse de doctorat.
Collection
Publications
Titre
Mechanisms of OGT-mediated HCF-1 protein maturation
Auteur(s)
Bhuiyan T.
Directeur(s)
Herr W.
Institution
Université de Lausanne, Faculté de biologie et médecine
Adresse
Faculté de biologie et de médecineUniversité de LausanneCH-1015 LausanneSUISSE
Statut éditorial
Acceptée
Date de publication
06/2015
Langue
anglais
Nombre de pages
193
Résumé
Post-translational protein modifications are crucial for many fundamental cellular and extracellular processes and greatly contribute to the complexity of organisms. Human HCF-1 is a transcriptional co-regulator that undergoes complex protein maturation involving reversible and irreversible post-translational modifications. Upon synthesis as a large precursor protein, HCF-1 undergoes extensive reversible glycosylation with β-N-acetylglucosamine giving rise to O-linked-β-N-acetylglucosamine (O-GlcNAc) modified serines and threonines. HCF-1 also undergoes irreversible site-specific proteolysis, which is important for one of HCF-1's major functions - the regulation of the cell-division cycle. HCF-1 O-GlcNAcylation and site-specific proteolysis are both catalyzed by a single enzyme with an unusual dual enzymatic activity, the O-GlcNAc transferase (OGT). HCF-1 is cleaved by OGT at any of six highly conserved 26 amino acid repeated sequences (HCF-1PRO repeats), but the mechanisms and the substrate requirements for OGT-mediated cleavage are not understood. In the present work, I characterized substrate requirements for OGT-mediated cleavage and O-GlcNAcylation of HCF-1. I identified key elements within the HCF-1PRO-repeat sequence that are important for proteolysis. Remarkably, an invariant single amino acid side-chain within the HCF-1PRO-repeat sequence displays particular OGT-binding properties and is essential for proteolysis. Additionally, I characterized substrate requirements for proteolysis outside of the HCF-1PRO repeat and identified a novel, highly O-GlcNAcylated OGT-binding sequence that enhances cleavage of the first HCF-1PRO repeat. These results link OGT association and its O-GlcNAcylation activities to HCF-1PRO-repeat proteolysis.
Mots-clé
HCF-1, OGT, O-GlcNAcylation, proteolysis, protein-protein interactions, crystal structure
Création de la notice
03/09/2015 15:41
Dernière modification de la notice
03/03/2018 16:04
Données d'usage