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 (
Address: Art Horwich
145 Boyer Center for Molecular Medicine
Phone: (203) 737-4431
FAX: (203)
737-1761
e-mail: arthur.horwich@yale.edu
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
(
Publications
Other Web Resources:
Boyer Center for Molecular Medicine
Center for Structural Biology
Howard Hughes Medical Institute
The Scripps Research Institute
X-ray Facility
Yale School of Medicine
Yale University
Lab People:
Adrian Apetri, Postdoc, BCMM 143
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Eli Chapman, Asst. Prof., Scripps ----------------------------------858-784-7387
George Farr, Staff Scientist, BCMM 143 -----------------------------737-4428
Wayne Fenton, Res. Scientist, BCMM 143 ---------------------------737-4428
Scripps
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Krystyna Furtak, Res. Tech., BCMM 145 ----------------------------737-4431
Art Horwich, Prof., BCMM 145 ------------------------------------------737-4431
Scripps
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Steve Johnson, Postdoc, BCMM 160-----------------------------------737-4431
Maria Nagy, Postdoc, BCMM 143--------------------------------------737-4428
Navneet Tyagi, Postdoc, BCMM 143 ----------------------------------737-4428
Jiou Wang, Postdoc, BCMM 145 ----------------------------------------737-4431
Note that some of us are located (full or part-time) at The Scripps
Research Institute in
If you have comments or suggestions, email me at wayne.fenton@yale.edu
phone: 203-737-4431
fax: 203-737-1761