Arthur L. Horwich | |
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Born | 1951 (age 72–73) |
Nationality | American |
Alma mater | Brown University |
Known for | uncovering chaperonin action |
Awards |
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Scientific career | |
Fields | Biology |
Institutions | |
Notable students | Tapan K. Chaudhuri [1] |
Arthur L. Horwich (born 1951) is an American biologist and Sterling Professor of Genetics and Pediatrics at the Yale School of Medicine. [2] [3] Horwich has also been a Howard Hughes Medical Institute investigator since 1990. [4] His research into protein folding uncovered the action of chaperonins, protein complexes that assist the folding of other proteins; Horwich first published this work in 1989. [5] [6]
For his scientific work Horwich has been awarded the Gairdner International Award (2004), Louisa Gross Horwitz Prize (2008), Lasker Award (2011), [7] Shaw Prize (2012), Albany Medical Center Prize (2016), and Breakthrough Prize (2020). He is a member of the National Academy of Sciences and the American Academy of Arts and Sciences. [8] [9]
Horwich was born in 1951. He grew up in Oak Park, west of Chicago. [10] In 1969, he entered Brown University as part of a new program that combined the undergraduate degree with medical school. [10] During medical school, Horwich studied fat cell metabolism in the laboratory of John Fain. Horwich received his A.B. in biomedical sciences in 1972 and his M.D. in 1975. [2] [4] He graduated as valedictorian of the first class to complete the combined program. [10] Horwich went on to do an internship and residency in pediatrics at Yale University. Midway through, Horwich was not sure about an entirely clinical future. After completing his residency, he joined the Salk Institute for Biological Studies in La Jolla, California for a postdoctoral position in molecular biology and virology. [10] At Salk, he worked in Walter Eckhart's laboratory alongside Tony Hunter and witnessed Hunter's discovery of tyrosine phosphorylation. [10] He credits this time with sharpening his skills as a scientist. He said, "Tony taught me the nuts and bolts of thinking about a problem." [10]
In 1981, Horwich moved back to New Haven, Connecticut for a postdoctoral fellowship at Yale University School of Medicine. He worked in the laboratory of Leon Rosenberg. [11]
In 1984, he moved across the hall from Rosenberg's lab to start his own laboratory as an assistant professor in the department of genetics. He still collaborated with members of the Rosenberg laboratory, including Wayne Fenton. As an independent researcher, Horwich asked whether the pathway that imports an enzyme called ornithine transcarbamylase (OTC) into the mitochondria of mammalian cells also could work in yeast. In 1987, during a genetic screen in yeast, Horwich and his colleagues stumbled across a protein folding function inside mitochondria. In the mutant strain, proteins entered mitochondria from the cytosol normally but then misfolded and aggregated. They named the protein encoded by the affected gene HSP60, Heat shock protein 60, because it has a mass of 60 kDa and is produced in larger quantity in response to heat. Hsp60 is found in an 850 kDa double ring assembly, each ring containing 7 copies of Hsp60. Such assemblies, known as chaperonins, also exist in other cellular compartments and are essential components, mediating protein folding under both heat shock and normal conditions. [12]
Since 1987, Horwich and his colleagues have been studying these molecules both in vivo and in vitro, with particular emphasis on the Hsp60 homologue in E. coli known as GroEL. They 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.
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In molecular biology, molecular chaperones are proteins that assist the conformational folding or unfolding of large proteins or macromolecular protein complexes. There are a number of classes of molecular chaperones, all of which function to assist large proteins in proper protein folding during or after synthesis, and after partial denaturation. Chaperones are also involved in the translocation of proteins for proteolysis.
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GroEL is a protein which belongs to the chaperonin family of molecular chaperones, and is found in many bacteria. It is required for the proper folding of many proteins. To function properly, GroEL requires the lid-like cochaperonin protein complex GroES. In eukaryotes the organellar proteins Hsp60 and Hsp10 are structurally and functionally nearly identical to GroEL and GroES, respectively, due to their endosymbiotic origin.
HSP60, also known as chaperonins (Cpn), is a family of heat shock proteins originally sorted by their 60kDa molecular mass. They prevent misfolding of proteins during stressful situations such as high heat, by assisting protein folding. HSP60 belong to a large class of molecules that assist protein folding, called molecular chaperones.
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The heat shock response (HSR) is a cell stress response that increases the number of molecular chaperones to combat the negative effects on proteins caused by stressors such as increased temperatures, oxidative stress, and heavy metals. In a normal cell, proteostasis must be maintained because proteins are the main functional units of the cell. Many proteins take on a defined configuration in a process known as protein folding in order to perform their biological functions. If these structures are altered, critical processes could be affected, leading to cell damage or death. The heat shock response can be employed under stress to induce the expression of heat shock proteins (HSP), many of which are molecular chaperones, that help prevent or reverse protein misfolding and provide an environment for proper folding.
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