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Expression, Detergent Solubilization, and Purification of a Membrane Transporter, the MexB Multidrug Resistance Protein
Published on: December 3, 2010
Function, evolution and structure of multidrug resistance protein (MRP)
1Cancer Research Laboratories, Queen's University, Kingston, Ontario, Canada.
Abstract:
Multidrug Resistance Protein (MRP) confers resistance to natural product drugs when overexpressed in cultured cells. It has also been detected in human tumors and in some cases, expression has been correlated with a poor response to chemotherapy. MRP is present in normal tissues where it probably functions as an active transporter of amphiphilic anions. It is also presumed to transport the drugs to which it confers resistance, but how and in what form has not been resolved. Unlike other members of the ATP Binding Cassette superfamily, MRP and several related proteins have three potential membrane spanning domains. The additional NH2-proximal domain in MRP contains five membrane spanning helices with an extracytosolic NH2-terminus and is essential for transport. Conserved features of gene organization and protein structure suggest that MRP and its related proteins share their ancestry with the cystic fibrosis conductance regulator.
Insights
Multidrug Resistance Protein (MRP) overexpression in cells causes resistance to natural drugs and is linked to poor chemotherapy response in tumors. MRP likely transports drugs and anions, with a unique structure essential for its function.
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Biology
Background:
- Multidrug Resistance Protein (MRP) is implicated in drug resistance when overexpressed in cultured cells.
- MRP is found in human tumors, with expression correlating to poor chemotherapy outcomes.
- In normal tissues, MRP likely functions as an active transporter for amphiphilic anions.
Purpose of the Study:
- To investigate the role of Multidrug Resistance Protein (MRP) in drug resistance.
- To understand the transport mechanism and structural features of MRP.
- To explore the evolutionary relationship of MRP with other ATP Binding Cassette superfamily members.
Main Methods:
- Analysis of MRP expression in cultured cells and human tumors.
- Investigation of MRP's transport activity for drugs and anions.
- Structural analysis of MRP, focusing on its membrane-spanning domains.
- Comparative analysis of gene organization and protein structure with related proteins.
Main Results:
- MRP overexpression confers resistance to natural product drugs.
- MRP's unique NH2-proximal domain with five membrane-spanning helices is essential for transport.
- MRP shares conserved features with the cystic fibrosis conductance regulator, suggesting a common ancestry.
Conclusions:
- MRP plays a significant role in multidrug resistance and impacts chemotherapy efficacy.
- The distinct structural domain of MRP is critical for its transporter function.
- MRP belongs to a protein family with evolutionary links to the cystic fibrosis conductance regulator.
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