Table 1 ClC-Kb mutations involved in the Bartter syndrome type 3 with available experimental data.
Variant | Protein region (residue distance to the pore) | Experimental Remaining current | Polyphen2.0 Probability of Damage | PoPMuSIC ΔΔG (kcal.mol−1) | FoldX/ENCoM ΔΔG (kcal.mol−1) | Exposition to solvent | ConSurf Scale | Interactive structural analysis of the 3D model |
|---|---|---|---|---|---|---|---|---|
G246R | α helix I (~10 Å) | None | Probably damaging | 0.89 | 2.35 | Buried | 8 | Steric clashes, charged residue in the protein core, possible disruption of the dimer |
A349D | K-L loop (~4 Å) | None | Probably damaging | 0.84 | 2.48 | Buried | 8 | Charged residue in the protein core and clashes with surrounding side chains |
R438C | α helix N (~14 Å) | None | Probably damaging | 0.99 | 0.96 | Buried | 7 | Loss of a salt-bridge with E442 |
R438H | α helix N (~14 Å) | None | Probably damaging | 0.30 | 0.32 | Buried | 7 | Steric clashes in a packed environment |
L439P | α helix N (~15 Å) | None | Probably damaging | 2.95 | 2.52 | Exposed to the membrane | 7 | Introduce a proline inside an α-helix |
G424E | M-N loop (~0 Å) | None | Probably damaging | 2.07 | 2.84 | Buried | 9 | Serious clashes in a packed environment, charged residue in the protein core (part of the pore) |
A204T | α helix G (~9 Å) | 0 to 25% | Probably damaging | 0.86 | 0.84 | Buried | 6 | Steric clashes, could push away the α helix G from the α helix F (part of the pore) |
P124L | α helix D (~0 Å) | 0 to 73% | Probably damaging | 0.01 | −0.13 | Partially exposed | 7 | Some steric clashes, perturbs the E125-K527 salt bridge (part of the pore), removal of a Pro at the beginning of the helix |
T115P | α helix C (~8 Å) | 18% | Probably damaging | 0.90 | 1.28 | Exposed | 5 | Add a proline at the end of an α-helix |
Y432H | α helix N (~4 Å) | 20% | Possibly damaging | 1.86 | 1.33 | Exposed to the membrane | 4 | Charged residue in contact with the membrane lipids |
L139P | D-E loop (~6 Å) | 27% | Probably damaging | 2.35 | 1.13 | Partially exposed | 7 | Destabilization of the D-E loop and disruption of the E136-R182 salt-bridge |
L81P | α helix B (~21 Å) | 35% | Probably damaging | 1.99 | 1.87 | Exposed to the membrane | 5 | Proline inside the α-helix |
A210V | α helix G (~7 Å) | 50% | Probably damaging | 1.01 | 0.47 | Buried | 7 | Some steric clashes in a relatively packed environment. Moderate damage of the protein function |
G120R | C-D loop (~1 Å) | 60% | Probably damaging | 0.67 | 0,05 | Exposed | 8 | Disruption of the E125-R527 salt bridge (nearby the pore). Partially tolerated |
V170M | α helix F (~3 Å) | 60% | Probably damaging | 0.91 | −0.56 | Buried | 9 | Minor steric clashes, pushes away helices involved in the pore |
R351W | K-L loop (~4 Å) | 60% | Probably damaging | 0.21 | 0.65 | Exposed | 3 | Loss of a salt bridge with E390 but the change could be tolerated |
R351P | K-L loop (~4 Å) | 63% | Probably damaging | 1.44 | 1.95 | Exposed | 3 | Loss of a salt-bridge with E390 and destabilization of the L-M loop |
R92W | α helix C (~20 Å) | 67% | Probably damaging | 0.41 | 0.51 | Exposed | 5 | Modification of electrostatic interactions in the B-C loop |
