ABCC8 p.Ser1356Cys
| Predicted by SNAP2: | A: N (97%), C: N (82%), D: N (97%), E: N (97%), F: N (87%), G: N (97%), H: N (97%), I: N (93%), K: N (97%), L: N (93%), M: N (97%), N: N (97%), P: N (93%), Q: N (97%), R: N (97%), T: N (97%), V: N (93%), W: N (72%), Y: N (93%), |
| Predicted by PROVEAN: | A: N, C: D, D: N, E: N, F: D, G: N, H: N, I: D, K: N, L: D, M: N, N: N, P: N, Q: N, R: N, T: N, V: N, W: D, Y: D, |
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[hide] Functional clustering of mutations in the dimer in... J Biol Chem. 2008 Oct 31;283(44):30322-9. Epub 2008 Aug 20. Masia R, Nichols CG
Functional clustering of mutations in the dimer interface of the nucleotide binding folds of the sulfonylurea receptor.
J Biol Chem. 2008 Oct 31;283(44):30322-9. Epub 2008 Aug 20., [PMID:18715873]
Abstract [show]
ATP-sensitive K(+) (K(ATP)) channels modulate their activity as a function of inhibitory ATP and stimulatory Mg-nucleotides. They are constituted by two proteins: a pore-forming K(+) channel subunit (Kir6.1, Kir6.2) and a regulatory sulfonylurea receptor (SUR) subunit, an ATP-binding cassette (ABC) transporter that confers MgADP stimulation to the channel. Channel regulation by MgADP is dependent on nucleotide interaction with the cytoplasmic nucleotide binding folds (NBF1 and NBF2) of the SUR subunit. Crystal structures of bacterial ABC proteins indicate that NBFs form as dimers, suggesting that NBF1-NBF2 heterodimers may form in SUR and other eukaryotic ABC proteins. We have modeled SUR1 NBF1 and NBF2 as a heterodimer, and tested the validity of the predicted dimer interface by systematic mutagenesis. Engineered cysteine mutations in this region have significant effects, both positive and negative, on MgADP stimulation of K(ATP) channels in excised patches and on macroscopic channel activity in intact cells. Additionally, the mutations cluster in the model structure according to their functional effect, such that patterns of alteration emerge. Of note, three gain-of-function mutations, leading to MgADP hyperstimulation of the channel, are located in the D-loop region at the center of the predicted dimer interface. Overall, the data support the idea that SUR1 NBFs assemble as heterodimers and that this interaction is functionally critical.
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No. Sentence Comment
84 Consistent with expectations, two mutations that increased MgADP stimulation (A1510C and S1511C) also increased diazoxide stimulation; a mutation that decreased MgADP stimulation (D1513C) also decreased diazoxide stimulation; and a mutation that had no effect on MgADP stimulation (S1356C) had no effect on diazoxide stimulation (Fig. 2C).
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ABCC8 p.Ser1356Cys 18715873:84:282
status: NEW85 Consistent with expectations, two mutations that increased MgADP stimulation (A1510C and S1511C) also increased diazoxide stimulation; a mutation that decreased MgADP stimulation (D1513C) also decreased diazoxide stimulation; and a mutation that had no effect on MgADP stimulation (S1356C) had no effect on diazoxide stimulation (Fig. 2C).
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ABCC8 p.Ser1356Cys 18715873:85:282
status: NEW