The multidrug resistance-associated protein (MRP) subfamily of the ATP-binding cassette (ABC) transporters plays a key role in protecting cells from drugs and environmental toxins such as heavy metals (mercury, arsenic, lead, and cadmium). The MRPs (also called ABCCs) are distinguished from other ABC transporters by two striking hallmarks: 1) they contain an additional """"""""N-terminal extension"""""""" with a conserved region called L0, and 2) they transport substrates in the form of glutathione (GSH)-conjugates or complexes. Here, we will use the powerful genetic, molecular, and cellular tools available in Saccharomyces cerevisiae to address several key issues of the MRPs.
Our specific aims are to: 1) determine whether conserved residues within the L0 of MRPs are specific for GSH binding; 2) assess whether novel interactors, recently identified for the yeast MRP Ycflp, play an integral role in the general mechanism of MRP transport; and 3) test the possibility that a major role of the MRP's is to dispose of potentially harmful """"""""metabolic detritus"""""""", using genetic and chemical screens. Overall, our analysis may suggest more effective therapies for MRP- based diseases (e.g. DJS, PXE, cystic fibrosis) and/or aid in reducing damage from environmental toxins.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32GM077024-02
Application #
7173736
Study Section
Special Emphasis Panel (ZRG1-F05 (20))
Program Officer
Okita, Richard T
Project Start
2005-12-01
Project End
2007-01-31
Budget Start
2006-12-01
Budget End
2007-01-31
Support Year
2
Fiscal Year
2007
Total Cost
$10,738
Indirect Cost
Name
Johns Hopkins University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Paumi, Christian M; Chuk, Matthew; Chevelev, Igor et al. (2008) Negative regulation of the yeast ABC transporter Ycf1p by phosphorylation within its N-terminal extension. J Biol Chem 283:27079-88
Paumi, Christian M; Menendez, Javier; Arnoldo, Anthony et al. (2007) Mapping protein-protein interactions for the yeast ABC transporter Ycf1p by integrated split-ubiquitin membrane yeast two-hybrid analysis. Mol Cell 26:15-25