Abstract: Series 108, Lecture 5

The Harvey Lectures Series 108 (2012—2013)

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Lecture #5: Thursday, March 21, 2013 — Watch Video of Lecture

Chaperonin-assisted protein folding:
“Nature leaves nothing to chance”

Arthur L Horwich, MD

Arthur L Horwich, MD

Sterling Professor of Genetics
Professor of Pediatrics
Investigator, Howard Hughes Medical Institute

Howard Hughes Medical Institute, Yale University School of Medicine

New Haven, Connecticut

Dr Horwich's Website

The astonishing ribonuclease refolding experiment of Anfinsen and his coworkers in the late 1950s made clear that the primary sequence of a polypeptide chain contains all of the information to guide it to the native active form. But not all proteins can spontaneously refold in vitro in such an experiment, instead forming misfolded aggregates. Likewise, expression of many eukaryotic proteins in bacteria results in inactive, aggregated forms. The notion of kinetic assistance to protein folding was intimated by Anfinsen himself - he at one point drew a blob for a “machine” that could “template” non-native proteins, but he could not decipher what feature would be universally recognized. The discovery in yeast of a mutant that blocked refolding of imported proteins demonstrated that folding is, in fact, assisted in the cell and that there is a shared feature recognized by a beautiful machine that Nature has devised to solve the kinetic difficulty of protein folding to the native state. I review the history of the discovery and subsequent elucidation of mechanism and then address the nature of the many neurodegenerative diseases associated with protein misfolding.