Mutant cycles at CFTR's non-canonical ATP-binding site support little interface separation during gating (original) (raw)

2011, Journal of General Physiology

CFTR, whose failure causes cystic fibrosis (Riordan et al., 1989), belongs to the ATP-binding cassette (ABC) transporter superfamily. Although most ABC transporters use the energy derived from ATP binding and hydrolysis for active transport across membranes, in CFTR, the binding and hydrolysis of ATP drive channel gating (Muallem and Vergani, 2009). Like other ABC transporters, CFTR consists of two homologous halves, each containing a cytosolic ABC, otherwise known as a nucleotide-binding domain (NBD) and a transmembranespanning domain (Locher, 2009). NBDs are highly conserved among all ABC proteins, containing several conserved motifs, including the Walker A and B motifs (Walker et al., 1982) in a RecA-like subdomain ("head") and the signature sequence (LSGGQXXR) in a helical subdomain ("tail"; e.g., Hung et al., 1998; Karpowich et al., 2001). High resolution crystal structures of ABC transporters and isolated NBD dimers reveal that in ATP-bound crystals, NBDs can form tight "head-to-tail" dimers (e.g.,