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Mutational analysis of polar amino acid residues within predicted transmembrane helices of Multidrug Resistance Protein 1 (ABCC1): Effect on substrate specificity
Author(s) -
Zhang DaWei,
Cole Susan P.C.,
Deeley Roger G.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a196-a
Subject(s) - abcc1 , transmembrane domain , atp binding cassette transporter , transmembrane protein , context (archaeology) , chemistry , mutagenesis , biochemistry , transport protein , multiple drug resistance , amino acid , transporter , biophysics , biology , mutation , gene , receptor , paleontology , antibiotics
Human Multidrug Resistance Protein1 (MRP1) is an ATP Binding Cassette (ABC) transporter that confers resistance to many natural product chemotherapeutic agents and can transport structurally diverse conjugated organic anions. In addition to two cytoplasmic nucleotide binding domains (NBDs), MRP1 has three polytopic membrane‐spanning domains (MSDs) with a total of 17 transmembrane (TM) helices. Using site‐directed mutagenesis, we demonstrated that certain polar residues within a number of TM helices are determinants of MRP1 substrate specificity or overall activity. For example, mutations T550A and T556A in TM10, N597A and S605A in TM11, E1089Q and K1092 in TM14, as well as Y1236F and T1241A in TM17 only modulated the drug resistance profile of MRP1. In contrast, Y568A in TM10, S1097A and N1100A in TM14, as well as T1242A in TM17 only altered the ability of MRP1 to transport the conjugated organic anion, 17β‐estradiol 17‐(β‐D‐glucuronide) (E 2 17βG). On the other hand, some mutations, such as N590A in TM11, D1084N in TM14, and Y1243F in TM17 affected overall activity of the protein. The location of these functionally important residues in TM helices will be discussed in the context of an energy‐minimized model of the membrane‐spanning domains of MRP1 in the presentation.