Abstract

Quality control pathways monitor the folding and assembly of newly synthesized secretory and membrane proteins, retaining some abnormal proteins in the endoplasmic reticulum and diverting others for degradation by cytoplasmic proteasomes. The operation of these quality control pathways underlies the cellular basis of human genetic diseases like cystic fibrosis that arise from mutations which alter the normal folding and assembly of integral membrane proteins. How the decision to degrade a misfolded or unassembled membrane protein is made, and the nature of the cellular machinery which recognizes and dislocates these proteins to cytoplasmic proteasomes for degradation is not known. Elucidating these processes is the long-term objective of the proposed research.
The specific aims constitute a comprehensive approach toward these goals by addressing four questions: (1) What is the molecular basis for CFTR misfolding? (2) How do cis-degradation signals determine the fate of integral membrane proteins? (3) What is the nature of the membrane apparatus through which integral membrane proteins are dislocated from the ER? (4) What is the role of cytoplasmic factors in dislocation of integral membrane proteins from the endoplasmic reticulum?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK043994-09
Application #
2908112
Study Section
Physical Biochemistry Study Section (PB)
Program Officer
Mckeon, Catherine T
Project Start
1991-05-01
Project End
2003-06-30
Budget Start
1999-07-01
Budget End
2000-06-30
Support Year
9
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
Stanford University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305

  Publications

Fayadat, Laurence; Kopito, Ron R (2003) Recognition of a single transmembrane degron by sequential quality control checkpoints. Mol Biol Cell 14:1268-78
Johnston, Jennifer A; Illing, Michelle E; Kopito, Ron R (2002) Cytoplasmic dynein/dynactin mediates the assembly of aggresomes. Cell Motil Cytoskeleton 53:26-38
Gelman, Marina S; Kannegaard, Elisa S; Kopito, Ron R (2002) A principal role for the proteasome in endoplasmic reticulum-associated degradation of misfolded intracellular cystic fibrosis transmembrane conductance regulator. J Biol Chem 277:11709-14
Illing, Michelle E; Rajan, Rahul S; Bence, Neil F et al. (2002) A rhodopsin mutant linked to autosomal dominant retinitis pigmentosa is prone to aggregate and interacts with the ubiquitin proteasome system. J Biol Chem 277:34150-60
Kopito, R R (1999) Biosynthesis and degradation of CFTR. Physiol Rev 79:S167-73
Yu, H; Kopito, R R (1999) The role of multiubiquitination in dislocation and degradation of the alpha subunit of the T cell antigen receptor. J Biol Chem 274:36852-8
Sato, S; Ward, C L; Kopito, R R (1998) Cotranslational ubiquitination of cystic fibrosis transmembrane conductance regulator in vitro. J Biol Chem 273:7189-92
Johnston, J A; Ward, C L; Kopito, R R (1998) Aggresomes: a cellular response to misfolded proteins. J Cell Biol 143:1883-98
Yu, H; Kaung, G; Kobayashi, S et al. (1997) Cytosolic degradation of T-cell receptor alpha chains by the proteasome. J Biol Chem 272:20800-4
Sato, S; Ward, C L; Krouse, M E et al. (1996) Glycerol reverses the misfolding phenotype of the most common cystic fibrosis mutation. J Biol Chem 271:635-8

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