ATP-Dependent Signaling in Simulations of a Revised Model of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)
| Autor: | Guiying Cui, Ingeborg Schmidt-Krey, Nael A. McCarty, Daniel T. Infield, James C. Gumbart, Kerry M. Strickland, Gorman Stock, Hyea Hwang |
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| Rok vydání: | 2019 |
| Předmět: |
Models
Molecular Protein Conformation Intracellular Space Cystic Fibrosis Transmembrane Conductance Regulator 010402 general chemistry 01 natural sciences Cystic fibrosis Diffusion Adenosine Triphosphate Protein structure 0103 physical sciences Materials Chemistry medicine Humans Nucleotide Homology modeling Physical and Theoretical Chemistry chemistry.chemical_classification Sequence Homology Amino Acid 010304 chemical physics biology Chemistry medicine.disease Cystic fibrosis transmembrane conductance regulator 0104 chemical sciences Surfaces Coatings and Films Transmembrane domain Chloride channel Biophysics biology.protein Signal transduction Signal Transduction |
| Zdroj: | The Journal of Physical Chemistry B. 123:3177-3188 |
| ISSN: | 1520-5207 1520-6106 |
| DOI: | 10.1021/acs.jpcb.8b11970 |
| Popis: | Cystic fibrosis transmembrane conductance regulator (CFTR) is a member of the ATP-binding cassette (ABC) transporter superfamily that has uniquely evolved to function as a chloride channel. It binds and hydrolyzes ATP at its nucleotide binding domains to form a pore providing a diffusive pathway within its transmembrane domains. CFTR is the only known protein from the ABC superfamily with channel activity, and its dysfunction causes the disease cystic fibrosis. While much is known about the functional aspects of CFTR, significant gaps remain, such as the structure-function relationship underlying signaling of ATP binding. In the present work, we refined an existing homology model using an intermediate-resolution (9 Å) published cryo-electron microscopy map. The newly derived models have been simulated in equilibrium molecular dynamics simulations for a total of 2.5 μs in multiple ATP-occupancy states. Putative conformational movements connecting ATP binding with pore formation are elucidated and quantified. Additionally, new interdomain interactions between E543, K968, and K1292 have been identified and confirmed experimentally; these interactions may be relevant for signaling ATP binding and hydrolysis to the transmembrane domains and induction of pore opening. |
| Databáze: | OpenAIRE |
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