CFTR REVIEW PAGE BACK TO DIAGRAM
INTRACELLULAR SEQUENCE BETWEEN TM6 AND NBD1
TRQFPWAVQTWYDSLGAINKIQDFLQKQEYKTLEYNLT
TTEVVMENVTAFWEEGFGELFEKAKQNNNNRKTSNGDDSLFFSN
(amino acids 351 thru 432)
The only high-resolution structure of an ABC superfamily member (of which CFTR is a member) is for MsbA. This bacterial lipid transporter was crystallized by Chang and Roth and resolved to 4.5 Å resolution. It clearly shows the intracellular loops as having distinct alpha-helical structure, and the loop between TM6 and the NBD domain functioning as a bridge, or conduit, between the NBD domains and the transmembrane domains. This implies the intracellular loops are helping to transmit energy from ATP hydrolysis at the NBD domains into a structural change at the pore. Named the "intracellular domains" by the authors, the intracellular loop of MsbA corresponding to this ICL in CFTR (ICD3 in MsbA) exists as two alpha-helices connected by short loops, with the one just before the NBD domain being the most conserved in sequence among MDR-ABC transporters. It is found in direct contact with both ICD1 and ICD2 (which corresponds to ICL1 and ICL2 of CFTR). ICD3 in MsbA is from amino acids 304 thru 327, with the first alpha-helix consisting of 304-314 and the second from 318-327. Science 9/7/01, Vol 293 pgs 1793-1800
T351, R352, and Q353 are highly conserved among CFTR of different species, and has been theorized to perhaps form a loop back into the pore. This could narrow the lumen of the pore and would account for mutations in these residues affecting chloride current flow as well as anion selectivity.
Another highly conserved sequence of amino acids in this area are Q359, T360, W361, Y362, and D363. Interestingly, there is also another area like this immediately following TM12 in the C-terminal half of CFTR. It is L1156, M1157, R1158, S1159, V1160.