Obiettivo The misfolded, unfolded or unassembled proteins in the Endoplasmic Reticulum (ER) are degraded by the “Protein Quality Control Mechanism” named as ER-associated degradation (ERAD). In addition to its safeguard role, ERAD can regulate physiological processes that occur in the ER, for example degradation of HMG–CoA reductase, the key enzyme of cholesterol synthesis. ERAD is a multistep process, which starts with substrate (unwanted protein) selection followed by ubiquitination, retrotranslocation, deglycosylation and proteasomal degradation. Aberrant ERAD has implications on several diseases, such as cystic fibrosis, a1-antitrypsin (AAT) deficiency, diabetes, neurodegenerative diseases and cancer.The details of ERAD mechanism are very well known through the studies in S.cerevisiae. Although the general scheme of the pathway is similar, ERAD is more complicated and highly regulated in mammals than in yeast. Studies in yeast suggested existence specialized ERAD pathways depending on the feature of the protein. These pathways are: ERAD-C ( for cytoplasmic misfolded domains), ERAD-L (for luminal misfolded regions), ERAD-M (for membrane misfolded regions). So far, this issue has not been studied in mammalian cells. Here, we intend to identify substrate specific differences present in retrotranslocation machineries in mammalian ERAD using four substrates with different structural features. Additionally, the effect of SVIP (the first identified endogenous ERAD inhibitor) on these substrates, the role of Npl4 in gp78-mediated ERAD and possible functional interaction of gp78 and hHrd1 enzymes will be examined. This research will provide the first information on the substrate specific differences of mammalian ERAD, and also the functional interaction between two important ER-resident E3s: gp78 and Hrd1. Our results on substrate specific ERAD mechanism would contribute to the studies on the therapies of diseases such as cystic fibrosis and AAT deficiency. Campo scientifico medical and health sciencesclinical medicineendocrinologydiabetesmedical and health sciencesclinical medicineoncologynatural sciencesbiological scienceszoologymammalogynatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes Programma(i) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Argomento(i) FP7-PEOPLE-2009-RG - Marie Curie Action: "Reintegration Grants" Invito a presentare proposte FP7-PEOPLE-IRG-2008 Vedi altri progetti per questo bando Meccanismo di finanziamento MC-IRG - International Re-integration Grants (IRG) Coordinatore EGE UNIVERSITY Contributo UE € 100 000,00 Indirizzo EGE UNIVERSITESI KAMPUSU 35100 İzmir Turchia Mostra sulla mappa Regione Ege İzmir İzmir Tipo di attività Higher or Secondary Education Establishments Contatto amministrativo Aysun Pabuccuoglu (Prof.) Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Costo totale Nessun dato
