Ron Kopito

Honors and Awards

• Established Investigator, American Heart Association (1993)
• Presidential Young Investigator, National Science Foundation (1989)
• Scholar in Biomedical Science, Lucille P. Markey Foundation (1985)
• Basil O'Connor Award, March of Dimes (1989)

Professional Education

Postdoctoral Advisees

Jiwon Hwang,  James Olzmann,  Margaret Pearce,  Caleb Richter,  Bianca Schrul

Graduate & Fellowship Program Affiliations

• Biochemistry
• Neurosciences
• Cell Biology

Internet Links

• Kopito Lab

Current Research Interests

Our lab studies the cellular mechanisms that monitor protein biogenesis and ensure that only properly folded and assembled proteins are deployed within the cell. Proteins that fail to fold or assemble correctly can acquire alternative conformations that may give rise to highly toxic products. Therefore, cells contain machinery to recognize and destroy malfolded proteins. Mutations and genetic polymorphisms can result in the synthesis of misfolded polypeptides. Human genetic diseases therefore constitute a fertile source of naturally occurring mutants that provide insight into the nature of these “quality control” mechanisms. Both cis-acting mutations that directly affect the production of correctly assembled proteins and trans-acting mutations that affect the function of the cellular quality control machinery are linked to such diverse genetic disorders as cystic fibrosis and Lou Gehrig’s and Huntington’s diseases.
Research in the Kopito lab is focused on two general questions:
(1) How do cells make sure that only structurally “correct” proteins are deployed? How do cells discriminate between folded and misfolded
proteins? Genetic biochemical and cell biological approaches are used to identify the machinery involved in recognizing and destroying misfolded proteins.
(2) How do misfolded proteins acquire toxic properties that lead to cell death and ultimately to neurodegeneration? What mechanisms do neurons have to suppress the formation of such toxic conformers and why in some cases do these mechanisms fail? Biochemical biophysical and genetic approaches ranging from fluorescence spectroscopy to the creation of transgenic and knockout mice are applied to address these
questions.

Publications

• Prion-like transmission of protein aggregates in neurodegenerative diseases. Brundin P, Melki R, Kopito R. Nat Rev Mol Cell Biol. 2010; 11 (4): 301-7
• Cytoplasmic penetration and persistent infection of mammalian cells by polyglutamine aggregates. Ren PH, Lauckner JE, Kachirskaia I, Heuser JE, Melki R, Kopito RR. Nat Cell Biol. 2009; 11 (2): 219-25
• Hypothalamic neurodegeneration and adult-onset obesity in mice lacking the Ubb polyubiquitin gene. Ryu KY, Garza JC, Lu XY, Barsh GS, Kopito RR. Proc Natl Acad Sci U S A. 2008; 105 (10): 4016-21
• OS-9 and GRP94 deliver mutant alpha1-antitrypsin to the Hrd1-SEL1L ubiquitin ligase complex for ERAD. Christianson JC, Shaler TA, Tyler RE, Kopito RR. Nat Cell Biol. 2008; 10 (3): 272-82
• Global changes to the ubiquitin system in Huntington's disease. Bennett EJ, Shaler TA, Woodman B, Ryu KY, Zaitseva TS, Becker CH, Bates GP, Schulman H, Kopito RR. Nature. 2007; 448 (7154): 704-8