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INTRACELLULAR LOOP 2
RMMMKYRDQRAGKISERLVITSEMIENIQSVKAYCWEEAMEKMIENLRQTELKLTRKAAYVRYFNS
(amino acids 242 thru 307)
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. Also called the "intracellular domains", the intracellular loop of MsbA corresponding to ICL2 in CFTR (ICD2 in MsbA) & consists mostly of alpha-helical residues (amino acids 193 thru 207 and 237 thru 252). The electron densities for amino acids 208 to 236 were found to be diffuse within the crystal structure. Science 9/7/01, Vol 293 pgs 1793-1800
It has been established that a loss of 19 amino acids in this loop results in a processing mutant. This implies that intracellular loop 2 is involved in protein folding in the ER. This is similar to the cardiac isoform deletion mutant (intracellular loop 1) expressed in epithelial cells. Purified CFTR with this 19 amino acid deletion in intracellular loop 2 have a subconductance state of 6 pS and this subconductance is exhibited more frequently than in wild type. Otherwise, it has usual properties. Intracellular loops have been shown to be important in gating in other ion channels.
There is at least one known CF-causing mutation in this loop.
Generally, mutations in the intracellular loops 1 and 2 tend to affect the pore such that there was an increased closed time, while mutations in intracellular loops 3 and 4 seem to be involved in decreasing the time the channel is open. Perhaps 1 and 2 help open the pore and 3 and 4 help keep it open. It's speculated that these loops help couple the NBDs to channel gating.