ABCC8 p.Ser1482Arg
| Predicted by SNAP2: | A: D (75%), C: D (75%), D: D (91%), E: D (85%), F: D (85%), G: D (85%), H: D (85%), I: D (85%), K: D (91%), L: D (80%), M: D (80%), N: D (85%), P: D (91%), Q: D (85%), R: D (85%), T: D (80%), V: D (80%), W: D (91%), Y: D (85%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, T: D, V: D, W: D, Y: D, |
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[hide] KATP channel interaction with adenine nucleotides. J Mol Cell Cardiol. 2005 Jun;38(6):907-16. Epub 2005 Feb 5. Matsuo M, Kimura Y, Ueda K
KATP channel interaction with adenine nucleotides.
J Mol Cell Cardiol. 2005 Jun;38(6):907-16. Epub 2005 Feb 5., [PMID:15910875]
Abstract [show]
ATP-sensitive potassium (K(ATP)) channels are regulated by adenine nucleotides to convert changes in cellular metabolic levels into membrane excitability. Hence, elucidation of interaction of SUR and Kir6.x with adenine nucleotides is an important issue to understand the molecular mechanisms underlying the metabolic regulation of the K(ATP) channels. We analyzed direct interactions with adenine nucleotides of each subunit of K(ATP) channels. Kir6.2 binds adenine nucleotides in a Mg(2+)-independent manner. SUR has two NBFs which are not equivalent: NBF1 is a Mg(2+)-independent high affinity nucleotide binding site, whereas NBF2 is a Mg-dependent low affinity site. Although SUR has ATPase activity at NBF2, it is not used to transport substrates against the concentration gradient unlike other ABC proteins. The ATPase cycle at NBF2 serves as a sensor of cellular metabolism. This may explain the low ATP hydrolysis rate compared to other ABC proteins. Based on studies of photoaffinity labeling, a model of K(ATP) channel regulation is proposed, in which K(ATP) channel activity is regulated by SUR via monitoring the intracellular MgADP concentration. K(ATP) channel activation is expected to be induced by the cooperative interaction of ATP binding at NBF1 and MgADP binding at NBF2.
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No. Sentence Comment
184 Mutations within the ABC signature motif of NBF2 of SUR1 (S1482R) and SUR2B (S1446R) abolished the channel activation by MgADP, whereas the corresponding mutation of NBF1 of SUR1 (S830R) and SUR2B (S809R) did not [96].
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ABCC8 p.Ser1482Arg 15910875:184:58
status: NEW[hide] Mutations in the linker domain of NBD2 of SUR inhi... EMBO J. 2002 Aug 15;21(16):4250-8. Matsuo M, Dabrowski M, Ueda K, Ashcroft FM
Mutations in the linker domain of NBD2 of SUR inhibit transduction but not nucleotide binding.
EMBO J. 2002 Aug 15;21(16):4250-8., [PMID:12169627]
Abstract [show]
ATP-sensitive potassium (K(ATP)) channels are composed of an ATP-binding cassette (ABC) protein (SUR1, SUR2A or SUR2B) and an inwardly rectifying K(+) channel (Kir6.1 or Kir6.2). Like other ABC proteins, the nucleotide binding domains (NBDs) of SUR contain a highly conserved "signature sequence" (the linker, LSGGQ) whose function is unclear. Mutation of the conserved serine to arginine in the linker of NBD1 (S1R) or NBD2 (S2R) did not alter the ability of ATP or ADP (100 microM) to displace 8-azido-[(32)P]ATP binding to SUR1, or abolish ATP hydrolysis at NBD2. We co-expressed Kir6.2 with wild-type or mutant SUR in Xenopus oocytes and recorded the resulting currents in inside-out macropatches. The S1R mutation in SUR1, SUR2A or SUR2B reduced K(ATP) current activation by 100 microM MgADP, whereas the S2R mutation in SUR1 or SUR2B (but not SUR2A) abolished MgADP activation completely. The linker mutations also reduced (S1R) or abolished (S2R) MgATP-dependent activation of Kir6.2-R50G co-expressed with SUR1 or SUR2B. These results suggest that the linker serines are not required for nucleotide binding but may be involved in transducing nucleotide binding into channel activation.
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149 Table I. Percentage of photoaf®nity labelling by 8-azido-[a-32P]ATP remaining after displacement with unlabelled ATP or ADP NBD1 (%) NBD2 (%) ATP ADP ATP ADP SUR1 12 T 10 21 T 14 52 T 11 45 T 11 SUR1-S830R 8 T 3.7 25 T 9.0 43 T 11 33 T 6.8 SUR1-S1482R 9 T 5.1 21 T 11 39 T 14 34 T 8.4 Values are expressed as a percentage of 8-azido-[a-32P]ATP bound in the absence of unlabelled ATP (100 mM) or ADP (100 mM).
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ABCC8 p.Ser1482Arg 12169627:149:249
status: NEW239 Mutations in the NBD2 linker were: SUR1-S1482R and SUR2-S1446R (S2R); SUR1-Q1426A, SUR1-H1537A.
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ABCC8 p.Ser1482Arg 12169627:239:40
status: NEW260 Crude membranes, containing similar amounts of wild-type SUR1, SUR1-S830R and SUR1-S1482R, as determined by western blotting, were incubated with 50 mM 8-azido- [a-32P]ATP or 50 mM 8-azido-[g-32P]ATP (ICN Biomedicals) in the presence or absence of 100 mM ATP or 100 mM ADP in 3 ml of TEM buffer (40 mM Tris±HCl pH 7.5, 0.1 mM EGTA and 1 mM MgSO4) containing 2 mM ouabain.
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ABCC8 p.Ser1482Arg 12169627:260:83
status: NEW