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Welcome to the home page of the Horwich lab at Yale School of Medicine, Dept. of Genetics, and Howard Hughes Medical Institute. We're interested in a family of molecular machines called chaperonins that mediate ATP-dependent protein folding in the cell.? We are also studying protein misfolding and the role of chaperones in neurodegenerative disease, in particular Lou Gehrig’s Disease (ALS).

Address:    Art Horwich
                YaleSchoolof Medicine
                 145 Boyer Center for Molecular Medicine
                295 Congress Ave.
                New Haven CT, 06510

Phone:   (203) 737-4431
FAX:      (203) 737-1761
e-mail:   arthur.horwich@yale.edu

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In 1987, during a genetic screen in yeast, we stumbled across a protein folding function inside mitochondria.  In the mutant strain, proteins  entered mitochondria from the cytosol normally but then misfolded and aggregated. The gene affected encoded a 60 kDa protein that we named Hsp60 because it was mildly heat inducible. Hsp60 is found in an 850 kDa double ring assembly, each ring containing 7 copies of Hsp60.

Such assemblies, called chaperonins, also exist in other cellular compartments and are essential components, mediating protein folding under both heat shock and normal conditions. Ever since 1987, we've been studying these fascinating molecules both in vivo and in vitro, with particular emphasis on the Hsp60 homologue in E. coli known as GroEL.  We and others found early on that a chaperonin-mediated folding reaction can be reconstituted in a test tube, and that has enabled structural and functional studies that have begun to explain how chaperonins work. In particular, a combination of crystallographic studies, with the late Paul Sigler's group here at Yale, and functional studies, using dynamic studies of a variety of mutant chaperonins, have begun to reveal how these chaperonins work.  The schematic diagram below summarizes our current view of the chaperonin-mediated protein folding pathway.

In a second related area, we have become interested in understanding a set of human neurodegenerative disorders in which proteins that share no common primary or secondary structure misfold and aggregate, in many cases forming amyloid fibrils. We are focusing on misfolding and aggregation of SOD1, superoxide dismutase, in inherited forms of amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease), where motor neurons become dysfunctional and die. A range of genetic and biochemical approaches are being taken in attempts to understand the pathophysiology of this disease using a transgenic mouse model system.


Other Web Resources:
Boyer Center for Molecular Medicine
Center for Structural Biology
Howard Hughes Medical Institute
The Scripps Research Institute
Yale School of Medicine
Yale University

Lab People:

 Urmi Bandyopadhyay, Postdoc, BCMM 143 --------------------------737-4428

 Wayne Fenton, Res. Scientist, BCMM 143 ---------------------------737-4428

 Krystyna Furtak, Res. Specialist., BCMM 145 ----------------------737-4431

Muhamed Hadzipasic, MSTP student, BCMM 145------------------737-4431

 Art Horwich, Prof., BCMM 145 ------------------------------------------737-4431

 Di Li, Res. Tech. , BCMM 145 -------------------------------------------737-4431

 Maria Nagy, Postdoc, BCMM 143---------------------------------------737-4428

 Weiming Ni, Postdoc, BCMM 145 ---------------------------------------737-4431

Yuyu Song, Postdoc, BCMM 145------------------------------------------737-4431

Eleanor Thomas, MSTP student, BCMM 143-------------------------737-4428

If you have comments or suggestions, email me at  wayne.fenton@yale.edu


phone: 203-737-4431
fax: 203-737-1761