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Protein folding, quality control and degradation in the endoplasmic reticulum

Persone

 

Molinari M.

(Responsabile)

Abstract

About 30% of the mammalian proteins are synthesized by ribosomes attached at the cytosolic face of the endoplasmic reticulum (ER) membrane. These polypeptides enter co-translationally in the ER lumen, which contains resident molecular chaperones and folding factors that assist their maturation. Native proteins are transported through the secretory pathway at their final intra- or extra-cellular destination. Terminally misfolded polypeptides are translocated across the ER membrane and are destroyed by cytosolic proteasomes. Cell and organism proteostasis relies on a balanced activity of the ER folding, quality control and degradation machineries. The aim of our work is to understand, at the molecular level, how protein biogenesis and quality control function and are regulated in the mammalian ER. There are several open questions remaining in the field and those addressed in our lab are: 1. What distinguishes folding intermediates to be retained in the folding environment from misfolded conformers to be eventually cleared from the mammalian ER lumen? 2. What determines the duration of the folding attempts phase after which newly synthesized polypeptides are eventually selected for ER-associated degradation? 3. What regulates the extraction of non-native proteins from the folding machinery? 4. How do physico-chemical properties of select polypeptides determine the engagement of specific folding, quality control or disposal pathways? To address these questions, we have produced more than 50 folding-competent and folding-defective model proteins specifically designed in our lab to determine, in the living cell, how variations in their physico-chemical properties affect the folding, quality control or disposal machineries engaged in the ER lumen, their folding rate and efficiency, their degradation rate and efficiency, the proneness to form soluble or insoluble aggregates. We are in the best position to address these issues since we have a proven expertise in the analysis of the mechanisms that regulate protein folding and quality control in mammalian cells, the technical capacity and the equipment to perform the relevant experiments. We believe that a thorough knowledge of the processes and of the factors determining the fate of newly synthesized polypeptides in the ER lumen will eventually allow manipulation of protein folding, quality control and degradation events. This will be instrumental to delay progression or even to cure diseases caused by inefficient functioning of the cellular protein factory, by expression of mutated proteins, or by pathogens that hijack these machineries. It will also ameliorate our capacity to produce high amounts of active recombinant proteins to be employed in the clinics and in the industry.

Informazioni aggiuntive

Data d'inizio
01.04.2012
Data di fine
31.07.2015
Durata
40 Mesi
Enti finanziatori
SNSF
Stato
Concluso
Categoria
Swiss National Science Foundation / Project Funding / Division III - Biology and Medicine