GRADUATE STUDENT ASSOCIATION

 

Colloquium Schedule: Fall 2010

November 10th

Dr. Arthur Horwich, Professor of Genetics and Pediatrics at Yale University, New Haven, CT

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Title: Protein Folding in the Cell and Misfolding in SOD1-linked ALS

 

Abstract

The final step of information transfer in the cell entails the folding of newly-synthesized proteins into their native form.  While the primary sequence of a polypeptide contains all of the information to direct folding to the native state, as shown by Anfinsen and his coworkers in the late 1950s, under cellular conditions many proteins are subject to off-pathway misfolding and to irreversible aggregation, in some cases associated with disease.  It turns out that cells have evolved a specialized protein machinery, molecular chaperones, designed to prevent such processes from occurring.  During a genetic screen in yeast we stumbled onto one of these “machines”, a chaperonin, that assists the folding of proteins newly-imported into mitochondria, which we called Hsp60.  Using subsequent genetic, biochemical, and biophysical approaches on the homologous bacterial system, the GroEL/GroES chaperonin system, we have, with our collaborators, been uncovering the mechanism by which this system provides essential kinetic assistance to protein folding.  More recently we have begun to explore how protein misfolding can lead to neurodegeneration.  Such behavior in the cytosol is particularly surprising, considering that a host of chaperone systems are present in that compartment.  We have been focusing on the effects of misfolding of the abundant cytosolic enzyme superoxide dismutase 1 (SOD1), affected in ~2% of ALS cases, modeling the misbehavior of a mutant form of this enzyme in C.elegans and mouse.

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Updated 11/03/2010