Analysis of Sequence Divergence in Mammalian ABCGs Predicts a Structural Network of Residues That Underlies Functional Divergence |
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| Authors: | James I Mitchell-White Thomas Stockner Nicholas Holliday Stephen J Briddon Ian D Kerr |
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| Affiliation: | 1.School of Life Sciences, University of Nottingham, Queen’s Medical Centre, Nottingham NG7 2UH, UK; (N.H.); (S.J.B.);2.Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, The Midlands, Nottingham NG7 2UH, UK;3.Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, Währingerstrasse 13A, 1090 Vienna, Austria; |
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| Abstract: | The five members of the mammalian G subfamily of ATP-binding cassette transporters differ greatly in their substrate specificity. Four members of the subfamily are important in lipid transport and the wide substrate specificity of one of the members, ABCG2, is of significance due to its role in multidrug resistance. To explore the origin of substrate selectivity in members 1, 2, 4, 5 and 8 of this subfamily, we have analysed the differences in conservation between members in a multiple sequence alignment of ABCG sequences from mammals. Mapping sets of residues with similar patterns of conservation onto the resolved 3D structure of ABCG2 reveals possible explanations for differences in function, via a connected network of residues from the cytoplasmic to transmembrane domains. In ABCG2, this network of residues may confer extra conformational flexibility, enabling it to transport a wider array of substrates. |
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| Keywords: | ABC transporter multidrug resistance membrane protein functional divergence ABCG2 |
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