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Institute for Research in Biomedicine
Istituto di Ricerca in Biomedicina

Via Vincenzo Vela 6 - CH-6500 Bellinzona
Tel. +41 91 820 0300 - Fax +41 91 820 0302 - info [at] irb [dot] usi [dot] ch

Substrate-Specific Mechanisms of Protein Degradation from the ER

Research area: Protein Folding and Quality Control

Group leaders: Maurizio Molinari


Status: In progress

Misfolded polypeptides produced in the ER are dislocated across the ER membrane to be degraded by cytosolic 26S-proteasomes in processes collectively defined as ERAD. Dislocation across the ER membrane is regulated by multimeric complexes built around one of the several membrane-embedded E3 ubiquitin ligases expressed in the mammalian ER. Physico-chemical features of the misfolded polypeptide (e.g. presence/absence of N-linked oligosaccharides, disulfide bonds, peptidyl-prolyl bonds in the cis conformation, membrane-anchor) may determine the quality control machineries that deliver the misfolded polypeptide at specific dislocation complexes. The definition of the rules that govern protein biogenesis and quality control requires a systematic analysis of appositely designed model folding-competent and folding-defective proteins. We have therefore prepared more than 50 model substrates with select physico-chemical features, whose fate will be monitored in mammalian cultured cells. The model polypeptides recapitulate structural defects found in mutant products of genes causing human disorders such as Alzheimer’s, Parkinson’s, Huntington’s diseases as well as many other rare genetic disorders characterized by gain-of-toxic-function or loss-of-function phenotypes. How the polypeptide’s features determine engagement of specific folding, quality control and degradation pathways will be determined in molecular details.

Merulla et al., Traffic. 2013; 14:767-777.