Regulation of function by dimerization through the amino-terminal membrane-spanning domain of human ABCC1/MRP1

J Biol Chem. 2007 Mar 23;282(12):8821-30. doi: 10.1074/jbc.M700152200. Epub 2007 Jan 30.

Abstract

Overexpression of some ATP-binding cassette (ABC) membrane transporters such as ABCB1/P-glycoprotein/MDR1 and ABCC1/MRP1 causes multidrug resistance in cancer chemotherapy. It has been thought that half-ABC transporters with one nucleotide-binding domain and one membrane-spanning domain (MSD) likely work as dimers, whereas full-length transporters with two nucleotide-binding domains and two or three MSDs function as monomers. In this study, we examined the oligomeric status of the human full-length ABC transporter ABCC1/MRP1 using several biochemical approaches. We found 1) that it is a homodimer, 2) that the dimerization domain is located in the amino-terminal MSD0L0 (where L0 is loop 0) region, and 3) that MSD0L0 has a dominant-negative function when coexpressed with wild-type ABCC1/MRP1. These findings suggest that ABCC1/MRP1 may exist and function as a dimer and that MSD0L0 likely plays some structural and regulatory functions. It is also tempting to propose that the MSD0L0-mediated dimerization may be targeted for therapeutic development to sensitize ABCC1/MRP1-mediated drug resistance in cancer chemotherapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Biological Transport
  • Cell Line
  • Cell Membrane / metabolism
  • Chromatography, Gel
  • Cross-Linking Reagents / pharmacology
  • Dimerization
  • Drug Resistance, Neoplasm*
  • Humans
  • Models, Biological
  • Multidrug Resistance-Associated Proteins / chemistry*
  • Multidrug Resistance-Associated Proteins / metabolism
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Tertiary
  • Sucrose / pharmacology
  • Transfection

Substances

  • Cross-Linking Reagents
  • Multidrug Resistance-Associated Proteins
  • Sucrose
  • multidrug resistance-associated protein 1