Key Documents

Ron Kopito

Professor, Biology (School of Humanities and Sciences)
Member, Bio-X

Contact Information

Clinical Offices
Academic Offices

Personal Information
Email KOPITO@stanford.edu

Administrative Contact
Tammy Learned Adminstrative Assistant Email tlearned@stanford.edu Tel Work 650 725-4845

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

A.B., Bowdoin College Biochemistry (1976)
Ph.D., MIT Biochemistry (1982)

Postdoctoral Advisees

Mark Hipp, Stephen Kaiser, Jane Lauckner, James Olzmann, Margaret Pearce, Caleb Richter, Brigit Riley, Ryan Tyler

Graduate & Fellowship Program Affiliations

Web Site Links

Kopito Lab

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

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
Central pore residues mediate the p97/VCP activity required for ERAD. DeLaBarre B, Christianson JC, Kopito RR, Brunger AT. Mol Cell. 2006; 22 (4): 451-62
HDAC6 and microtubules are required for autophagic degradation of aggregated huntingtin. Iwata A, Riley BE, Johnston JA, Kopito RR. J Biol Chem. 2005; 280 (48): 40282-92
Global impairment of the ubiquitin-proteasome system by nuclear or cytoplasmic protein aggregates precedes inclusion body formation. Bennett EJ, Bence NF, Jayakumar R, Kopito RR. Mol Cell. 2005; 17 (3): 351-65
Impairment of the ubiquitin-proteasome system by protein aggregation. Bence NF, Sampat RM, Kopito RR. Science. 2001; 292 (5521): 1552-5
The mouse polyubiquitin gene Ubb is essential for meiotic progression. Ryu KY, Sinnar SA, Reinholdt LG, Vaccari S, Hall S, Garcia MA, Zaitseva TS, Bouley DM, Boekelheide K, Handel MA, Conti M, Kopito RR. Mol Cell Biol. 2008; 28 (3): 1136-46
Misfolded proteins partition between two distinct quality control compartments. Kaganovich D, Kopito R, Frydman J. Nature. 2008; 454 (7208): 1088-95
Impaired post-translational folding of familial ALS-linked Cu, Zn superoxide dismutase mutants. Bruns CK, Kopito RR. EMBO J. 2007; 26 (3): 855-66
The mouse polyubiquitin gene UbC is essential for fetal liver development, cell-cycle progression and stress tolerance. Ryu KY, Maehr R, Gilchrist CA, Long MA, Bouley DM, Mueller B, Ploegh HL, Kopito RR. EMBO J. 2007; 26 (11): 2693-706
Ubiquitin-specific protease 2 as a tool for quantification of total ubiquitin levels in biological specimens. Ryu KY, Baker RT, Kopito RR. Anal Biochem. 2006; 353 (1): 153-5
Cellular mechanisms of protein quality control. Bennett EJ, Shaler T, Gonzalez-Zulueta M, Schulman HF, Iwata A, Riley BE, Johnston JA, Bucci M, Nukina N, Ellerby L, Kopito RR. Rinsho Shinkeigaku. 2006; 46 (11): 805
Intersecting pathways to neurodegeneration in Parkinson's disease: effects of the pesticide rotenone on DJ-1, alpha-synuclein, and the ubiquitin-proteasome system. Betarbet R, Canet-Aviles RM, Sherer TB, Mastroberardino PG, McLendon C, Kim JH, Lund S, Na HM, Taylor G, Bence NF, Kopito R, Seo BB, Yagi T, Yagi A, Klinefelter G, Cookson MR, Greenamyre JT. Neurobiol Dis. 2006; 22 (2): 404-20
Effect of ubiquitin expression on neuropathogenesis in a mouse model of familial amyotrophic lateral sclerosis. Gilchrist CA, Gray DA, Stieber A, Gonatas NK, Kopito RR. Neuropathol Appl Neurobiol. 2005; 31 (1): 20-33
Subversion of cellular autophagosomal machinery by RNA viruses. Jackson WT, Giddings TH, Taylor MP, Mulinyawe S, Rabinovitch M, Kopito RR, Kirkegaard K. PLoS Biol. 2005; 3 (5): e156
Suppression of wild-type rhodopsin maturation by mutants linked to autosomal dominant retinitis pigmentosa. Rajan RS, Kopito RR. J Biol Chem. 2005; 280 (2): 1284-91
Formation of morphologically similar globular aggregates from diverse aggregation-prone proteins in mammalian cells. Mukai H, Isagawa T, Goyama E, Tanaka S, Bence NF, Tamura A, Ono Y, Kopito RR. Proc Natl Acad Sci U S A. 2005; 102 (31): 10887-92
Application and analysis of the GFPu family of ubiquitin-proteasome system reporters. Bence NF, Bennett EJ, Kopito RR. Methods Enzymol. 2005; 399 481-90
Increased susceptibility of cytoplasmic over nuclear polyglutamine aggregates to autophagic degradation. Iwata A, Christianson JC, Bucci M, Ellerby LM, Nukina N, Forno LS, Kopito RR. Proc Natl Acad Sci U S A. 2005; 102 (37): 13135-40
Recognition of a single transmembrane degron by sequential quality control checkpoints. Fayadat L, Kopito RR. Mol Biol Cell. 2003; 14 (3): 1268-78
Cystic fibrosis: premature degradation of mutant proteins as a molecular disease mechanism. Gelman MS, Kopito RR. Methods Mol Biol. 2003; 232 27-37
The missing linker: an unexpected role for a histone deacetylase. Kopito RR, Mol Cell. 2003; 12 (6): 1349-51
Immunoglobulin light chains dictate vesicular transport-dependent and -independent routes for IgM degradation by the ubiquitin-proteasome pathway. Elkabetz Y, Kerem A, Tencer L, Winitz D, Kopito RR, Bar-Nun S. J Biol Chem. 2003; 278 (21): 18922-9
A principal role for the proteasome in endoplasmic reticulum-associated degradation of misfolded intracellular cystic fibrosis transmembrane conductance regulator. Gelman MS, Kannegaard ES, Kopito RR. J Biol Chem. 2002; 277 (14): 11709-14
Cysteine residues in the nucleotide binding domains regulate the conductance state of CFTR channels. Harrington MA, Kopito RR. Biophys J. 2002; 82 (3): 1278-92
Rescuing protein conformation: prospects for pharmacological therapy in cystic fibrosis. Gelman MS, Kopito RR. J Clin Invest. 2002; 110 (11): 1591-7
Cytoplasmic dynein/dynactin mediates the assembly of aggresomes. Johnston JA, Illing ME, Kopito RR. Cell Motil Cytoskeleton. 2002; 53 (1): 26-38
A rhodopsin mutant linked to autosomal dominant retinitis pigmentosa is prone to aggregate and interacts with the ubiquitin proteasome system. Illing ME, Rajan RS, Bence NF, Kopito RR. J Biol Chem. 2002; 277 (37): 34150-60
Specificity in intracellular protein aggregation and inclusion body formation. Rajan RS, Illing ME, Bence NF, Kopito RR. Proc Natl Acad Sci U S A. 2001; 98 (23): 13060-5
Aggresomes and Russell bodies. Symptoms of cellular indigestion? Kopito RR, Sitia R. EMBO Rep. 2000; 1 (3): 225-31
Conformational disease. Kopito RR, Ron D. Nat Cell Biol. 2000; 2 (11): E207-9
Formation of high molecular weight complexes of mutant Cu, Zn-superoxide dismutase in a mouse model for familial amyotrophic lateral sclerosis. Johnston JA, Dalton MJ, Gurney ME, Kopito RR. Proc Natl Acad Sci U S A. 2000; 97 (23): 12571-6
Aggresomes, inclusion bodies and protein aggregation. Kopito RR, Trends Cell Biol. 2000; 10 (12): 524-30
Biosynthesis and degradation of CFTR. Kopito RR, Physiol Rev. 1999; 79 (1 Suppl): S167-73
The role of multiubiquitination in dislocation and degradation of the alpha subunit of the T cell antigen receptor. Yu H, Kopito RR. J Biol Chem. 1999; 274 (52): 36852-8
Redox reagents and divalent cations alter the kinetics of cystic fibrosis transmembrane conductance regulator channel gating. Harrington MA, Gunderson KL, Kopito RR. J Biol Chem. 1999; 274 (39): 27536-44
Topology of the region surrounding Glu681 of human AE1 protein, the erythrocyte anion exchanger. Tang XB, Fujinaga J, Kopito R, Casey JR. J Biol Chem. 1998; 273 (35): 22545-53
Cotranslational ubiquitination of cystic fibrosis transmembrane conductance regulator in vitro. Sato S, Ward CL, Kopito RR. J Biol Chem. 1998; 273 (13): 7189-92
Aggresomes: a cellular response to misfolded proteins. Johnston JA, Ward CL, Kopito RR. J Cell Biol. 1998; 143 (7): 1883-98
Cytosolic pH regulates GCl through control of phosphorylation states of CFTR. Reddy MM, Kopito RR, Quinton PM. Am J Physiol. 1998; 275 (4 Pt 1): C1040-7
ER quality control: the cytoplasmic connection. Kopito RR, Cell. 1997; 88 (4): 427-30
A cluster of cytoplasmic histidine residues specifies pH dependence of the AE2 plasma membrane anion exchanger. Kobayashi S, Kopito RR. Cell. 1997; 90 (6): following 1159
Cytosolic degradation of T-cell receptor alpha chains by the proteasome. Yu H, Kaung G, Kobayashi S, Kopito RR. J Biol Chem. 1997; 272 (33): 20800-4
A cluster of cytoplasmic histidine residues specifies pH dependence of the AE2 plasma membrane anion exchanger. Sekler I, Kobayashi S, Kopito RR. Cell. 1996; 86 (6): 929-35
Immunocytochemical localization of vacuolar H+-ATPase and Cl--HCO3- anion exchanger (erythrocyte band-3 protein) in avian osteoclasts: effect of calcium-deficient diet on polar expression of the H+-ATPase pump. Bastani B, Ross FP, Kopito RR, Gluck SL. Calcif Tissue Int. 1996; 58 (5): 332-6
Glycerol reverses the misfolding phenotype of the most common cystic fibrosis mutation. Sato S, Ward CL, Krouse ME, Wine JJ, Kopito RR. J Biol Chem. 1996; 271 (2): 635-8
Failure of the cystic fibrosis transmembrane conductance regulator to conduct ATP. Reddy MM, Quinton PM, Haws C, Wine JJ, Grygorczyk R, Tabcharani JA, Hanrahan JW, Gunderson KL, Kopito RR. Science. 1996; 271 (5257): 1876-9
Conformational states of CFTR associated with channel gating: the role ATP binding and hydrolysis. Gunderson KL, Kopito RR. Cell. 1995; 82 (2): 231-9
Degradation of CFTR by the ubiquitin-proteasome pathway. Ward CL, Omura S, Kopito RR. Cell. 1995; 83 (1): 121-7
AE3 anion exchanger isoforms in the vertebrate retina: developmental regulation and differential expression in neurons and glia. Kobayashi S, Morgans CW, Casey JR, Kopito RR. J Neurosci. 1994; 14 (10): 6266-79
Intracellular turnover of cystic fibrosis transmembrane conductance regulator. Inefficient processing and rapid degradation of wild-type and mutant proteins. Ward CL, Kopito RR. J Biol Chem. 1994; 269 (41): 25710-8
Cl-/HCO3- exchange function differs in adult and fetal rat hippocampal neurons. Raley-Susman KM, Sapolsky RM, Kopito RR. Brain Res. 1993; 614 (1-2): 308-14
Cloning and characterization of band 3, the human erythrocyte anion-exchange protein (AE1). Lux SE, John KM, Kopito RR, Lodish HF. Proc Natl Acad Sci U S A. 1989; 86 (23): 9089-93
Identification of a 185-kDa band 3-related polypeptide in oxyntic cells. Thomas HA, Machen TE, Smolka A, Baron R, Kopito RR. Am J Physiol. 1989; 257 (3 Pt 1): C537-44
A 115-kD polypeptide immunologically related to erythrocyte band 3 is present in Golgi membranes. Kellokumpu S, Neff L, Jämsä-Kellokumpu S, Kopito R, Baron R. Science. 1988; 242 (4883): 1308-11
Cloning and characterization of a murine band 3-related cDNA from kidney and from a lymphoid cell line. Alper SL, Kopito RR, Libresco SM, Lodish HF. J Biol Chem. 1988; 263 (32): 17092-9
Structure and tissue-specific expression of the mouse anion-exchanger gene in erythroid and renal cells. Kopito RR, Andersson MM, Herzlinger DA, al-Awqati Q, Lodish HF. Soc Gen Physiol Ser. 1988; 43 151-61
A molecular biological approach to the study of anion transport. Alper SL, Kopito RR, Lodish HF. Kidney Int Suppl. 1987; 23 S117-33
Multiple tissue-specific sites of transcriptional initiation of the mouse anion antiport gene in erythroid and renal cells. Kopito RR, Andersson MA, Lodish HF. Proc Natl Acad Sci U S A. 1987; 84 (20): 7149-53
Structure and organization of the murine band 3 gene. Kopito RR, Andersson M, Lodish HF. J Biol Chem. 1987; 262 (17): 8035-40
Primary structure and transmembrane orientation of the murine anion exchange protein. Kopito RR, Lodish HF. Nature. 1985 Jul 18-24; 316 (6025): 234-8
Structure of the murine anion exchange protein. Kopito RR, Lodish HF. J Cell Biochem. 1985; 29 (1): 1-17
Radioenzymatic assay of plasma mevalonate. Parker TS, Kopito RR, Brunengraber H. Methods Enzymol. 1985; 110 58-71
The shunt pathway of mevalonate metabolism in the isolated perfused rat liver. Weinstock SB, Kopito RR, Endemann G, Tomera JF, Marinier E, Murray DM, Brunengraber H. J Biol Chem. 1984; 259 (14): 8939-44
The shunt pathway of mevalonate metabolism in the isolated perfused rat kidney. Kopito RR, Murray DM, Story DL, Brunengraber H. J Biol Chem. 1984; 259 (1): 372-7
Assessment of the flux of mitochondrial acetyl-CoA in liver and kidney by using the differential production of 14CO2 from tracers of (1-14C)- and (2-14C)-labelled 4-methyl-2-oxovalerate. Tomera JF, Kopito RR, Brunengraber H. Biochem J. 1983; 210 (1): 265-8
Metabolism of plasma mevalonate in rats and humans. Kopito RR, Weinstock SB, Freed LE, Murray DM, Brunengraber H. J Lipid Res. 1982; 23 (4): 577-83
Urinary clearance and metabolism of mevalonate by the isolataed perfused rat kidney. Brunengraber H, Weinstock SB, Story DL, Kopito RR. J Lipid Res. 1981; 22 (6): 916-20
(R)-mevalonate excretion in human and rat urines. Kopito RR, Brunengraber H. Proc Natl Acad Sci U S A. 1980; 77 (10): 5738-40
Sialoproteinaemia: lack of correlation with inhibition of in vitro lymphoblastosis induced by phytohaemagglutinin or alloantigen. Gray BN, Kopito RR, Anderson LL, Baralt OL, Connery CK, Watkins E. Clin Exp Immunol. 1976; 25 (2): 227-33