scholarly journals The molecular evolution of function in the CFTR chloride channel

2021 ◽  
Vol 153 (12) ◽  
Author(s):  
Daniel T. Infield ◽  
Kerry M. Strickland ◽  
Amit Gaggar ◽  
Nael A. McCarty

The ATP-binding cassette (ABC) transporter superfamily includes many proteins of clinical relevance, with genes expressed in all domains of life. Although most members use the energy of ATP binding and hydrolysis to accomplish the active import or export of various substrates across membranes, the cystic fibrosis transmembrane conductance regulator (CFTR) is the only known animal ABC transporter that functions primarily as an ion channel. Defects in CFTR, which is closely related to ABCC subfamily members that bear function as bona fide transporters, underlie the lethal genetic disease cystic fibrosis. This article seeks to integrate structural, functional, and genomic data to begin to answer the critical question of how the function of CFTR evolved to exhibit regulated channel activity. We highlight several examples wherein preexisting features in ABCC transporters were functionally leveraged as is, or altered by molecular evolution, to ultimately support channel function. This includes features that may underlie (1) construction of an anionic channel pore from an anionic substrate transport pathway, (2) establishment and tuning of phosphoregulation, and (3) optimization of channel function by specialized ligand–channel interactions. We also discuss how divergence and conservation may help elucidate the pharmacology of important CFTR modulators.

2017 ◽  
Author(s):  
Valentina Corradi ◽  
Ruo-Xu Gu ◽  
Paola Vergani ◽  
D. Peter Tieleman

ABSTRACTThe cystic fibrosis transmembrane conductance regulator (CFTR) is an ion channel that regulates the flow of anions across epithelia. Mutations in CFTR cause cystic fibrosis. CFTR belongs to the ATP-Binding Cassette (ABC) transporter superfamily, and gating is controlled by phosphorylation and ATP binding and hydrolysis. Recent ATP-free and ATP-bound structures of zebrafish CFTR revealed an unwound segment of transmembrane helix (TM) 8, which appears to be a unique feature of CFTR not present in other ABC transporter structures. Here, by means of 1 μs long molecular dynamics simulations, we investigate the interactions formed by this TM8 segment with nearby helices, in both ATP-free and ATP-bound states. We highlight the structural role of TM8 in maintaining the functional architecture of the pore and we describe a distinct membrane defect that is found near TM8 only in the ATP-free state. The results of the MD simulations are discussed in the context of the gating mechanism of CFTR.


2001 ◽  
Vol 42 (7) ◽  
pp. 1007-1017 ◽  
Author(s):  
Michael Dean ◽  
Yannick Hamon ◽  
Giovanna Chimini

2012 ◽  
Vol 5 (6) ◽  
pp. 930-939 ◽  
Author(s):  
L. He ◽  
J. Skirkanich ◽  
L. Moronetti ◽  
R. Lewis ◽  
T. Lamitina

2007 ◽  
Vol 282 (31) ◽  
pp. 22793-22803 ◽  
Author(s):  
Peter M. Jones ◽  
Anthony M. George

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