Chaperonin-mediated Protein Folding

Arthur L Horwich

doi:10.1074/jbc.x113.497321

Abstract

We have been studying chaperonins these past twenty years through an initial discovery of an action in protein folding, analysis of structure, and elucidation of mechanism. Some of the highlights of these studies were presented recently upon sharing the honor of the 2013 Herbert Tabor Award with my early collaborator, Ulrich Hartl, at the annual meeting of the American Society for Biochemistry and Molecular Biology in Boston. Here, some of the major findings are recounted, particularly recognizing my collaborators, describing how I met them and how our great times together propelled our thinking and experiments.

Highlights

My pathway to studying a protein folding machine could not have been predicted from the trajectory of my training
I cloned the cDNA for a nuclear-coded urea cycle enzyme, ornithine transcarbamylase (OTC), which is involved in an X-linked deficiency that results in lethal ammonia intoxication in newborn male infants
We soon showed that the targeting sequence contained sufficient information to direct mitochondrial localization because, when we fused it to the cytosolic protein dihydrofolate reductase (DHFR), it directed DHFR into mitochondria [3]

Summary

How I Came to Study a Machine That Assists Protein Folding

My pathway to studying a protein folding machine could not have been predicted from the trajectory of my training. I participated in early recombinant DNA-mediated expression of tumor virus-transforming proteins and watched Tony discover tyrosine phosphorylation [1]. I cloned the cDNA for a nuclear-coded urea cycle enzyme, ornithine transcarbamylase (OTC), which is involved in an X-linked deficiency that results in lethal ammonia intoxication in newborn male infants. It is a devastating clinical situation I indelibly observed during pediatric training. We soon showed that the targeting sequence contained sufficient information to direct mitochondrial localization because, when we fused it to the cytosolic protein dihydrofolate reductase (DHFR), it directed DHFR into mitochondria [3]. When I moved across the hall as an independent investigator in 1984, I wanted to isolate the “machinery” of the mitochondria themselves that was involved with protein import

Discovery of Chaperonin Action in Mediating Protein Folding

Structural Analyses