Structure of the cystic fibrosis transmembrane conductance regulator in the inward-facing conformation revealed by single particle electron microscopy

Ateeq Al-Zahrani; Natasha Cant; Vassilis Kargas; Tracy Rimington; Luba Aleksandrov; John R. Riordan; Robert C. Ford; Ateeq Al-Zahrani; Natasha Cant; Vassilis Kargas; Tracy Rimington; Luba Aleksandrov; John R. Riordan; Robert C. Ford

doi:10.3934/biophy.2015.2.131

AIMS Biophysics

2015, Volume 2, Issue 2: 131-152. doi: 10.3934/biophy.2015.2.131

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Research article Special Issues

Structure of the cystic fibrosis transmembrane conductance regulator in the inward-facing conformation revealed by single particle electron microscopy

1.
Faculty of Life Sciences, The University of Manchester, Manchester M13 9PT, UK;
2.
University College in Qunfudah, The University of Umm-Alqura, Kingdom of Saudi Arabia;
3.
Bioinformatics Institute, 30 Biopolis Street, #07-01 Matrix, 138671 Singapore;
4.
Department of Biochemsitry and Biophysics, University of North Carolina, Chapel Hill, 6107 Thurston-Bowles, Campus Box 7248, Chapel Hill, NC 27599, USA

Received: 16 February 2015 Accepted: 04 May 2015 Published: 13 May 2015

The most common inherited disease in European populations is cystic fibrosis. Mutations in the gene lead to loss of function of the cystic fibrosis transmembrane conductance regulator protein (CFTR). CFTR is a member of the ATP-binding cassette family of membrane proteins that mostly act as active transporters using ATP to move substances across membranes. These proteins undergo large conformational changes during the transport cycle, consistent with an inward-facing to outward-facing translocation mechanism that was originally proposed by Jardetzky. CFTR is the only member of this family of proteins that functions as an ion channel, and in this case ATP and phosphorylation of a regulatory domain controls the opening of the channel. In this article we describe the inward-facing conformation of the protein and show it can be modulated by the presence of a purified recombinant NHERF1-PDZ1 domain that binds with high affinity to the CFTR C-terminal PDZ motif (-QDTRL). ATP hydrolysis activity of CFTR can also be modulated by glutathione, which we postulate may bind to the inward-facing conformation of the protein. A homology model for CFTR, based on a mitochondrial ABC transporter of glutathione in the inward-facing configuration has been generated. The map and the model are discussed with respect to the biology of the channel and the specific relationship between glutathione levels in the cell and CFTR. Finally, disease-causing mutations are mapped within the model and discussed in terms of their likely physiological effects.

Keywords:

Citation: Ateeq Al-Zahrani, Natasha Cant, Vassilis Kargas, Tracy Rimington, Luba Aleksandrov, John R. Riordan, Robert C. Ford. Structure of the cystic fibrosis transmembrane conductance regulator in the inward-facing conformation revealed by single particle electron microscopy[J]. AIMS Biophysics, 2015, 2(2): 131-152. doi: 10.3934/biophy.2015.2.131

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Abstract

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