The peroxisome is a ubiquitous organelle of eukaryotic cells. It participates in a wide variety of metabolic processes and defects in peroxisome biogenesis are the cause of numerous human diseases. The peroxisome biogenesis disorders are one of these. These lethal inherited disorders are caused by defects in the biogenesis of the peroxisomes, which in turn results in the loss of virtually all peroxisomal metabolic functions. We and others have recently found that the proteins PEX3, PEX16 and PEX19 are required for the biogenesis of peroxisome membranes and that PEX11 proteins participate in the division of peroxisomes. These and other results have led to the proposal of a two pathway model of peroxisome biogenesis and the long-term objective of this proposal is to test this model of peroxisome membrane biogenesis. This will be accomplished through four specific aims. The first will involve the analysis of peroxisome membrane synthesis as mediated by PEX3, PEX16, and PEX19.
The second aims i nvolves an analysis of how PEX11a and PEX11b mediate peroxisome division. The third will involve the development of triply mutated cell lines for use in aim 1.
The fourth aim will be to identify the targeting signals that direct integral PMPs to the peroxisome and into the peroxisome membrane. The significance of these studies is that they will improve our understanding of eukaryotic cell biology and the molecular basis of human disease by testing our current hypotheses about the mechanisms of peroxisome membrane biogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK059479-02
Application #
6517894
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Haft, Carol R
Project Start
2001-05-01
Project End
2005-04-30
Budget Start
2002-05-01
Budget End
2003-04-30
Support Year
2
Fiscal Year
2002
Total Cost
$335,175
Indirect Cost
Name
Johns Hopkins University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Fang, Yi; Morrell, James C; Jones, Jacob M et al. (2004) PEX3 functions as a PEX19 docking factor in the import of class I peroxisomal membrane proteins. J Cell Biol 164:863-75
Jones, Jacob M; Morrell, James C; Gould, Stephen J (2004) PEX19 is a predominantly cytosolic chaperone and import receptor for class 1 peroxisomal membrane proteins. J Cell Biol 164:57-67
Erdmann, Ralf; Gould, Stephen J (2002) Visualization and purification of yeast peroxisomes. Methods Enzymol 351:365-81
Li, Xiaoling; Baumgart, Eveline; Morrell, James C et al. (2002) PEX11 beta deficiency is lethal and impairs neuronal migration but does not abrogate peroxisome function. Mol Cell Biol 22:4358-65
Li, Xiaoling; Baumgart, Eveline; Dong, Gao-Xiang et al. (2002) PEX11alpha is required for peroxisome proliferation in response to 4-phenylbutyrate but is dispensable for peroxisome proliferator-activated receptor alpha-mediated peroxisome proliferation. Mol Cell Biol 22:8226-40
Harper, Courtney C; South, Sarah T; McCaffery, J Michael et al. (2002) Peroxisomal membrane protein import does not require Pex17p. J Biol Chem 277:16498-504