include 2 transmembrane or membrane-spanning domains, 2 nucleotide-binding domains and a regulatory domain. The transmembrane domains are each connected to a nucleotide binding domain (NBD) in the cytoplasm. The first NBD is connected to the second transmembrane domain by a regulatory "R" domain that is a unique feature of CFTR, not present in other ABC transporters which carries 19 predicted sites for protein kinase A(PKA). Six of these have been reported to be phosphorylated in vivo. The ion channel only opens when its R-domain has been phosphorylated by PKA and ATP is bound at the NBDs. Phosphorylation displaces the disordered R domain from positions preventing NBD dimerization and opening. The amino-terminus is part of the lasso motif which anchors into the cell membrane. The carboxyl terminal of the protein is anchored to the cytoskeleton by a PDZ-interacting domain. The structure is shas(PDBitsI) shows a homopentameric assembly of mutated NBD1, the first nucleotide binding domain (NBD1) of the transporter Location and function The CFTR gene is made up of 27 exons that encode its gene makeup and is found on the long (q) arm of chromosome 7 at locus 31.2. Exons are DNA fragments that provide the code for a protein structure. CFTR functions as phosphorylation and ATP-gated anion channel, increasing the conductance for certain anions (e.g. Cl−) to flow down their electrochemical gradient. ATP-driven conformational changes in CFTR open and close a gate to allow the transmembrane flow of anions down their electrochemical gradient. This in contrast to other ABC proteins, in which ATP-driven conformational changes fuel uphill substrate transport across cellular membranes. Essentially, CFTR is an ion channel that evolved as a 'broken' ABC transporter that leaks when in the open conformation. CFTRs consist of five domains including two trans-membrane domains, each linked to a nucleotide-binding domain. CFTR also contains another domain called the regulatory domain. Other members of the ABC transporter superfamily are involved in the uptake of nutrients in prokaryotes, or in the export of a variety of substrates in eukaryotes. ABC transporters have evolved to transduce the free energy of ATP hydrolysis to the uphill movement of substrates across the cell membrane. They have two main conformations, one where the cargo binding site is facing the cytosol or inward facing (ATP free), and one where it is outward facing (ATP bound). ATP binds to each nucleotide-binding domain, which results in the subsequent NBD dimerization, leading to