ABCMdb

ABCC7 p.Met348Ile

ClinVar:	c.1043T>A , p.Met348Lys ? , not provided
CF databases:	c.1042A>G , p.Met348Val (CFTR1) ? , This mutation was identified in a CFTR gene mutation screening of 60 Patients with idiopathic chronic pancreatitis recruited from the region of North Rhine Westfalia in Germany. The entire coding region of the CFTR gene was sequenced. c.1043T>A , p.Met348Lys (CFTR1) ? , The mutation on the other chromosome is still unknown. This mutation was found on one chromosome while screening 56 Italian CF chromosomes. c.1043T>C , p.Met348Thr (CFTR1) ? , The mutation was detected by DGGE analysis and characterized by direct sequencing. We have seen it only twice, in over 1800 control chromosomes from Italian population.
Predicted by SNAP2:	A: D (71%), C: D (66%), D: D (85%), E: D (85%), F: D (63%), G: D (80%), H: D (80%), I: N (53%), K: D (85%), L: N (66%), N: D (71%), P: D (91%), Q: D (63%), R: D (85%), S: D (66%), T: D (75%), V: N (53%), W: D (80%), Y: D (75%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: N, G: D, H: D, I: N, K: D, L: N, N: D, P: D, Q: D, R: D, S: D, T: D, V: N, W: N, Y: N,

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Publications
[hide] Timing of CFTR Pore Opening and Structure of Its T... Cell. 2015 Oct 22;163(3):724-33. doi: 10.1016/j.cell.2015.09.052. Epub 2015 Oct 22. Sorum B, Czege D, Csanady L
Timing of CFTR Pore Opening and Structure of Its Transition State.
Cell. 2015 Oct 22;163(3):724-33. doi: 10.1016/j.cell.2015.09.052. Epub 2015 Oct 22., [PMID:26496611]

Abstract [show]
In CFTR, the chloride ion channel mutated in cystic fibrosis (CF) patients, pore opening is coupled to ATP-binding-induced dimerization of two cytosolic nucleotide binding domains (NBDs) and closure to dimer disruption following ATP hydrolysis. CFTR opening rate, unusually slow because of its high-energy transition state, is further slowed by CF mutation DeltaF508. Here, we exploit equilibrium gating of hydrolysis-deficient CFTR mutant D1370N and apply rate-equilibrium free-energy relationship analysis to estimate relative timing of opening movements in distinct protein regions. We find clear directionality of motion along the longitudinal protein axis and identify an opening transition-state structure with the NBD dimer formed but the pore still closed. Thus, strain at the NBD/pore-domain interface, the DeltaF508 mutation locus, underlies the energetic barrier for opening. Our findings suggest a therapeutic opportunity to stabilize this transition-state structure pharmacologically in DeltaF508-CFTR to correct its opening defect, an essential step toward restoring CFTR function.

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74 Timing of Motion at Position 348 in the Pore Region (A) Inward single-channel currents of the cut-DR(D1370N) CFTR background construct (top trace) and of channels bearing mutations M348I, M348K, M348C, M348N, and M348A, respectively, in the same background. Currents were recorded at 80 mV, in symmetrical 140 mM Cl ; dashes on the left mark zero-current level. Login to comment