Molecular Disruption of the Power Stroke in the ATP-binding Cassette Transport Protein MsbA*
| Autor: | Wilma Shi, Hendrik W. van Veen, Elizabeth V. Freeman, Lisa A. Fagg, Anam Ali, Rupak Doshi |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Models
Molecular Protein Conformation Blotting Western ATP-binding cassette transporter Plasma protein binding Biology Crystallography X-Ray Biochemistry Protein Structure Secondary Substrate Specificity Cell membrane Protein structure Adenosine Triphosphate Bacterial Proteins Membrane Biology medicine Escherichia coli Binding site Molecular Biology Binding Sites Cell Membrane Biological Transport Cell Biology Membrane transport Transport protein Protein Structure Tertiary Transmembrane domain Kinetics medicine.anatomical_structure Mutation Biophysics ATP-Binding Cassette Transporters Protein Multimerization Protein Binding |
| Popis: | ATP-binding cassette transporters affect drug pharmacokinetics and are associated with inherited human diseases and impaired chemotherapeutic treatment of cancers and microbial infections. Current alternating access models for ATP-binding cassette exporter activity suggest that ATP binding at the two cytosolic nucleotide-binding domains provides a power stroke for the conformational switch of the two membrane domains from the inward-facing conformation to the outward-facing conformation. In outward-facing crystal structures of the bacterial homodimeric ATP-binding cassette transporters MsbA from gram-negative bacteria and Sav1866 from Staphylococcus aureus, two transmembrane helices (3 and 4) in the membrane domains have their cytoplasmic extensions in close proximity, forming a tetrahelix bundle interface. In biochemical experiments on MsbA from Escherichia coli, we show for the first time that a robust network of inter-monomer interactions in the tetrahelix bundle is crucial for the transmission of nucleotide-dependent conformational changes to the extracellular side of the membrane domains. Our observations are the first to suggest that modulation of tetrahelix bundle interactions in ATP-binding cassette exporters might offer a potent strategy to alter their transport activity. |
| Databáze: | OpenAIRE |
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