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Arthur L. Horwich |
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| Professor of Genetics and Pediatrics; Associate Investigator, Howard Hughes Medical Institute |
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* A.B. Brown University 1972
* M.D. Brown University, 1975
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| Appointments: | |
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| Higgins Professor of Genetics and Pediatrics; Investigator, Howard Hughes Medical Institute
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| Research Interests: | |
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Chaperones in protein folding and unfolding
ALS (Lou Gehrig’s Disease)
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| Honors: | |
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Elected National Academy of Sciences, 2003
Gairdner International Award, 2004
Stein and Moore Award of The Protein Society, 2006
Wiley Prize in Biomedical Sciences, 2007
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| Current Research: | |
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| Studies of the past decade have shown that many diseases of
neurodegeneration are the result of protein misfolding, and we have begun to
seek an understanding of the mechanism of such degeneration. We have focused
on misfolding caused by mutant forms of the anti-oxidant cytosolic enzyme SOD
(superoxide dismutase), that produce an inherited form of ALS (Lou Gehrig’s
disease), with progressive and fatal motor neuron dysfunction. We are using
both C.elegans and mice expressing mutant SOD, and both genetic and
biochemical approaches, to investigate how mutant SOD produces motor neuron
dysfunction, and are seeking to identify ways to prevent or reverse this. We
are also beginning to examine other mouse mutants with inherited ALS, as well
as sporadic human ALS, with a view to gaining a broader understanding of
disease mechanism.
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| The chaperonin ring system carries out an essential step in
information transfer from DNA to effector protein, the final step of folding
of proteins to their native state. The kinetic assistance provided by these
megadalton assemblies is mediated by binding non-native forms in an open ring
containing a hydrophobic lining, preventing misfolding and aggregation from
occurring, followed by ATP-directed release of bound protein into a
now-encapsulated hydrophilic ring where productive folding occurs. Through
genetic, biochemical, EM, and X-ray studies, we know a great deal about the
states of the chaperonin machine itself (using the bacterial GroEL-GroES as
the model system), but the fate of the polypeptide “substrate” is not well
understood. For example, is binding in an open ring associated with unfolding?
We are currently seeking to address this using hydrogen exchange studies.
Does folding inside the assembly follow the same path as outside free in
solution? Does the chaperonin binding surface “adjust” upon binding a
non-native protein? A variety of spectroscopy techniques should allow us to
address these questions.
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| A second ring system we are studying carries out an exactly
opposite action on polypeptides. It takes a native folded protein and rips
apart its structure, feeding the polypeptide chain in a linear fashion into a
coaxially aligned garbage disposal that degrades it into small peptides. This
is the standard mechanism for degrading proteins in the living cell, employed
by the so-called proteasome in eukaryotic cells. We are studying a more
tractable bacterial model, the ClpA-ClpP system. How much ATP is used in
mediating this reaction? Does the ATP turnover increase when the machine is
actively unfolding and degrading a protein? Does the ATP turnover occur in a
rotary fashion or in a more randomized fashion around the 6-membered ClpA
ring? Can we “see” a protein get unraveled? Can we “watch” loop structures in
the central channel of ClpA pull on the substrate protein? How much force is
required to pull apart a native protein? These are all questions that are
under study using fluorescence and biochemical techniques, both ensemble and
single molecule, as well as stopped-flow techniques.
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| Representative Publications: | |
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| Park, E.S., Fenton, W.A., and Horwich, A.L. (2007) Disulfide
bond formation as probe of topology during folding in the GroEL-GroES chamber:
Correct formation of long-range bonds and editing of incorrect short-range
ones. Proc. Natl. Acad. Sci. USA 104, 2145-2150.
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| Farr, G.W., Fenton, W.A., and Horwich, A.L. (2007) Perturbed
ATPase activity and not “close confinement” of substrate in the cis cavity
affects rates of folding by tail-multiplied GroEL. Proc Natl Acad Sci USA 104,
5342-5347.
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| Elad, N., Farr, G.W., Clare, D.K., Orlova, E.V., Horwich, A.L.,
and Saibil, H.R. (2007) Topologies of a substrate protein bound to the
chaperonin GroEL. Mol Cell 26, 415-426.
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| Hinnerwisch, J., Fenton, W.A., Farr, G.W., Furtak, K., and
Horwich, A.L. (2005) Loops in the central channel of ClpA chaperone mediate
protein binding, unfolding, and translocation. Cell 121, 1029-1041.
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| Contact Information: | | |
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