This project will investigate an ABC-type of transport ATPase, DrrAB, that confers resistance to doxorubicin and daunorubicin in the producer organism Streptomyces peucetius. DrrAB consists of two subunits DrrA and DrrB. Interestingly, DrrA bears homology to P-glycoprotein, a multidrug resistance protein, and to other members of the ABC family including CFTR and ABC 1. DrrAB and Pgp are also functionally similar: both confer doxorubicin resistance, DrrAB in the producer organism and Pgp in cancer cells. Because of the sequence, structural and functional similarity between DrrAB and Pgp, it is likely that they share a common ancestor. Hence, elucidation of the function of 'Drr' and the nature of the drug binding sites in 'Drr' will shed light on the mechanism of function of Pgp and on the evolution of multidrug resistance. Furthermore, DrrAB is ideal for understanding interaction between the membrane domain and the catalytic domain of ABC transporters. Preliminary experiments have shown that DrrA and DrrB are biochemically coupled; DrrA is required for the stability and maintenance of DrrB in the membrane and DrrB is required for the activity of DrrA. Experiments will be designed to test the hypothesis that DrrA forms a complex with DrrB and protects it from proteolysis before DrrB is targeted to the membrane, Experiments to study interaction between the two subunits will consist of both biochemical and genetic approaches including isolation of interaction-defective mutants and the second-site suppressors. These studies will have relevance in understanding targeting of membrane proteins and in elucidating the role played by the catalytic domains in stabilizing the membrane domains of multidomain or multisubunit proteins.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Physical Biochemistry Study Section (PB)
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Chin, Jean
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Georgia State University
Schools of Arts and Sciences
United States
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Rahman, Sadia J; Kaur, Parjit (2018) Conformational changes in a multidrug resistance ABC transporter DrrAB: Fluorescence-based approaches to study substrate binding. Arch Biochem Biophys 658:31-45
Brown, Kenneth; Li, Wen; Kaur, Parjit (2017) Role of Aromatic and Negatively Charged Residues of DrrB in Multisubstrate Specificity Conferred by the DrrAB System of Streptomyces peucetius. Biochemistry 56:1921-1931
Zhang, Han; Rahman, Sadia; Li, Wen et al. (2015) Characterization of a novel domain 'GATE' in the ABC protein DrrA and its role in drug efflux by the DrrAB complex. Biochem Biophys Res Commun 459:148-53
Li, Wen; Sharma, Madhu; Kaur, Parjit (2014) The DrrAB efflux system of Streptomyces peucetius is a multidrug transporter of broad substrate specificity. J Biol Chem 289:12633-46
Li, Wen; Rao, Divya K; Kaur, Parjit (2013) Dual role of the metalloprotease FtsH in biogenesis of the DrrAB drug transporter. J Biol Chem 288:11854-64
Zhang, Han; Pradhan, Prajakta; Kaur, Parjit (2010) The extreme C terminus of the ABC protein DrrA contains unique motifs involved in function and assembly of the DrrAB complex. J Biol Chem 285:38324-36
Pradhan, Prajakta; Li, Wen; Kaur, Parjit (2009) Translational coupling controls expression and function of the DrrAB drug efflux pump. J Mol Biol 385:831-42
Rao, Divya K; Kaur, Parjit (2008) The Q-loop of DrrA is involved in producing the closed conformation of the nucleotide binding domains and in transduction of conformational changes between DrrA and DrrB. Biochemistry 47:3038-50
Kaur, Parjit; Rao, Divya K; Gandlur, Suvarna M (2005) Biochemical characterization of domains in the membrane subunit DrrB that interact with the ABC subunit DrrA: identification of a conserved motif. Biochemistry 44:2661-70