Role of transmembrane segment 5 and extracellular loop 3 in the homodimerization of human ABCC1.

Resistance to multiple anticancer agents is a major obstacle in the successful treatment of cancers. Overexpression of some ATP-binding cassette (ABC) membrane transporters such as ABCC1 has been shown to be a major contributor of multidrug resistance (MDR) in both laboratory cell line models and the clinical setting. ABCC1 has been thought to function as a homodimer with a putative dimerization domain located in the first 281 amino acid residues, including MSD0 and L0 domains. In this study, we further mapped in detail the dimerization site and placed it in TM5 and ECL3 in MSD0 using co-expression and co-immunoprecipitation of a series of deletion constructs. TM5 and ECL3 in one subunit appear to interact with TM5 and ECL3 in the opposing subunit in a sequence-independent manner, but their physical location together with the hydrophobicity of TM5 and the length of ECL3 appears to be important contributors to the dimerization ability of ABCC1.