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Differential mechanisms of Cantú syndrome-associated gain of function mutations in the ABCC9 (SUR2) subunit of the KATP channel.

Cooper PE, Sala-Rabanal M, Lee SJ, Nichols CG - J. Gen. Physiol. (2015)

Bottom Line: For P429L and A475V mutants, sensitivity to ATP inhibition was comparable to WT channels, but activation by MgADP was significantly greater.C1039Y-dependent channels were significantly less sensitive to inhibition by ATP or by glibenclamide, but MgADP activation was comparable to WT.The results indicate that these three CS mutations all lead to overactive K(ATP) channels, but at least two mechanisms underlie the observed gain of function: decreased ATP inhibition and enhanced MgADP activation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Cell Biology and Physiology, and Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, Saint Louis, MO 63110 Department of Cell Biology and Physiology, and Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, Saint Louis, MO 63110.

No MeSH data available.


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CS mutations in SUR2. (A) Alignment of SUR2 (ABCC9) with the multidrug ABC transporter Sav1866 (2ONJ) and heterodimeric ABC transporter TM287-TM288 (3QF4), upon which we built homology models. (B and C) Key structural domains TMD1 and 2 and NBD1 and 2 are indicated, as well as predicted α-helical (pink) and β-strand (green) segments. (B) Homology models of “open” and “closed” conformations of the SUR2A protein, which are based on Staphylococcus aureus Sav1866, a bacterial homologue of the human ABC transporter Mdr1 and heterodimeric ABC transporter TM287-TM288 (TM287/288) from Thermotoga maritime, respectively. Published CS mutations from previous reports are shown in green (open) and light pink (closed).
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fig1: CS mutations in SUR2. (A) Alignment of SUR2 (ABCC9) with the multidrug ABC transporter Sav1866 (2ONJ) and heterodimeric ABC transporter TM287-TM288 (3QF4), upon which we built homology models. (B and C) Key structural domains TMD1 and 2 and NBD1 and 2 are indicated, as well as predicted α-helical (pink) and β-strand (green) segments. (B) Homology models of “open” and “closed” conformations of the SUR2A protein, which are based on Staphylococcus aureus Sav1866, a bacterial homologue of the human ABC transporter Mdr1 and heterodimeric ABC transporter TM287-TM288 (TM287/288) from Thermotoga maritime, respectively. Published CS mutations from previous reports are shown in green (open) and light pink (closed).

Mentions: Models of human SUR2A (Fig. 1) were built using Modeller v9.8 from the template of the multidrug ABC transporter Sav1866 (2ONJ, to model the “open” conformation) and heterodimeric ABC transporter TM287-TM288 (3QF4, to model the “closed” conformation), respectively. The TM0 domain and L0 loop (1–281) were omitted because of lack of sequence homology to any proteins of known structure. Two extended loops unique to SUR2A were also omitted: one connecting TM1 and NBD1 (614–672) and a second connecting NBD1 and TM2 (920–966). A multiple sequence alignment (MSA) was performed using ClustalW2 between SUR2 and the two template sequences in conjunction with other proteins of the human ABCC family (ABCC1, 2, 3, 4, 5, 6, 8, and 10) for TM1 and NBD1 because of low sequence identity. High sequence identity enabled a reliable sequence alignment of TMD2 and NBD2 by MSA between SUR2 and SUR1, 2ONJ, and 3QF4.


Differential mechanisms of Cantú syndrome-associated gain of function mutations in the ABCC9 (SUR2) subunit of the KATP channel.

Cooper PE, Sala-Rabanal M, Lee SJ, Nichols CG - J. Gen. Physiol. (2015)

CS mutations in SUR2. (A) Alignment of SUR2 (ABCC9) with the multidrug ABC transporter Sav1866 (2ONJ) and heterodimeric ABC transporter TM287-TM288 (3QF4), upon which we built homology models. (B and C) Key structural domains TMD1 and 2 and NBD1 and 2 are indicated, as well as predicted α-helical (pink) and β-strand (green) segments. (B) Homology models of “open” and “closed” conformations of the SUR2A protein, which are based on Staphylococcus aureus Sav1866, a bacterial homologue of the human ABC transporter Mdr1 and heterodimeric ABC transporter TM287-TM288 (TM287/288) from Thermotoga maritime, respectively. Published CS mutations from previous reports are shown in green (open) and light pink (closed).
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4664827&req=5

fig1: CS mutations in SUR2. (A) Alignment of SUR2 (ABCC9) with the multidrug ABC transporter Sav1866 (2ONJ) and heterodimeric ABC transporter TM287-TM288 (3QF4), upon which we built homology models. (B and C) Key structural domains TMD1 and 2 and NBD1 and 2 are indicated, as well as predicted α-helical (pink) and β-strand (green) segments. (B) Homology models of “open” and “closed” conformations of the SUR2A protein, which are based on Staphylococcus aureus Sav1866, a bacterial homologue of the human ABC transporter Mdr1 and heterodimeric ABC transporter TM287-TM288 (TM287/288) from Thermotoga maritime, respectively. Published CS mutations from previous reports are shown in green (open) and light pink (closed).
Mentions: Models of human SUR2A (Fig. 1) were built using Modeller v9.8 from the template of the multidrug ABC transporter Sav1866 (2ONJ, to model the “open” conformation) and heterodimeric ABC transporter TM287-TM288 (3QF4, to model the “closed” conformation), respectively. The TM0 domain and L0 loop (1–281) were omitted because of lack of sequence homology to any proteins of known structure. Two extended loops unique to SUR2A were also omitted: one connecting TM1 and NBD1 (614–672) and a second connecting NBD1 and TM2 (920–966). A multiple sequence alignment (MSA) was performed using ClustalW2 between SUR2 and the two template sequences in conjunction with other proteins of the human ABCC family (ABCC1, 2, 3, 4, 5, 6, 8, and 10) for TM1 and NBD1 because of low sequence identity. High sequence identity enabled a reliable sequence alignment of TMD2 and NBD2 by MSA between SUR2 and SUR1, 2ONJ, and 3QF4.

Bottom Line: For P429L and A475V mutants, sensitivity to ATP inhibition was comparable to WT channels, but activation by MgADP was significantly greater.C1039Y-dependent channels were significantly less sensitive to inhibition by ATP or by glibenclamide, but MgADP activation was comparable to WT.The results indicate that these three CS mutations all lead to overactive K(ATP) channels, but at least two mechanisms underlie the observed gain of function: decreased ATP inhibition and enhanced MgADP activation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Cell Biology and Physiology, and Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, Saint Louis, MO 63110 Department of Cell Biology and Physiology, and Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, Saint Louis, MO 63110.

No MeSH data available.


Related in: MedlinePlus