Mechanism of chloride permeation in the cystic fibrosis transmembrane conductance regulator chloride channel.
The cystic fibrosis transmembrane conductance regulator (CFTR) functions as a Cl- channel important in transepithelial salt and water transport. While there is a paucity of direct structural information on CFTR, much has been learned about the molecular determinants of the CFTR Cl- channel pore region and the mechanism of Cl- permeation through the pore from indirect structure-function studies. The first and sixth transmembrane regions of the CFTR protein play major roles in forming the channel pore and determining its functional properties by interacting with permeating Cl- ions. Positively charged amino acid side-chains are involved in attracting negatively charged Cl- ions into the pore region, where they interact briefly with a number of discrete sites on the pore walls. The pore appears able to accommodate more than one Cl- ion at a time, and Cl- ions bound inside the pore are probably sensitive to one another's presence. Repulsive interactions between Cl- ions bound concurrently within the pore may be important in ensuring rapid movement of Cl- ions through the pore. Chloride ion binding sites also interact with larger anions that can occlude the pore and block Cl- permeation, thus inhibiting CFTR function. Other ions besides Cl- are capable of passing through the pore, and specific amino acid residues that may be important in allowing the channel to discriminate between different anions have been identified. This brief review summarizes these mechanistic insights and tries to incorporate them into a simple cartoon model depicting the interactions between the channel and Cl- ions that are important for ion translocation.
Linsdell
Paul
P
Department of Physiology & Biophysics, Dalhousie University, Halifax, Canada. paul.linsdell@dal.ca.
D000818:Animals; D001665:Binding Sites; D002712:Chlorides / Q000378:metabolism*; D003550:Cystic Fibrosis / Q000235:genetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology; D010539:Permeability; D011487:Protein Conformation
D002712:Chlorides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator