| Mutation (reference) . | Location in the OF state and movement in the elevator mechanism . | Elevator mechanism: Support, refute, or neutral? . |
|---|---|---|
| HS C479W (Chu et al., 2010) found in compound heterozygote with dRTA mutation G701D | C479 is near extracellular end of TM3, facing TM4 and TM8. It moves inward with the transport domain in the translocation event. | Neutral. Tryptophan substitution could disrupt packing near the ends of TM4 and TM3, which could propagate to the binding site, but there are no major conformational changes here in the elevator mechanism. |
| HSt R730C, S731P (Bruce et al., 2005; Guizouarn et al., 2007; Stewart et al., 2011) | At the N-terminal end of TM10, near the substrate-binding site and expected to move with the substrate and the rest of the transport domain. | Neutral. Mutations at these sites would be expected to affect transport for almost any mechanism. |
| HSt H734R, S762R (Bruce et al., 2005) | These two residues are close to each other in the OF state. | Neutral. Arginine substitution is expected to disrupt packing in the transport domain. |
| HS D705Y (Bruce et al., 2005; Guizouarn et al., 2007; Barneaud-Rocca et al., 2013), | Near the cytoplasmic end of transport TM9, facing TM2 and nonhelical residues leading to TM3. | Neutral. Tyrosine substitution would interfere with packing within the transport domain. |
| HSt L687P (Bruce et al., 2005; Guizouarn et al., 2007; Stewart et al., 2011) | Cytoplasmic end of TM8 (transport), near Q521 of TM5 (dimerization) and V513, I516 of short helix H2. L687 moves several angstroms away from Q521, V513, and I516 in the translocation event. | Support. Proline for leucine would cause a bend near the end of TM8. Moreover, the smaller side chain would also likely have weaker interactions with H2, therefore destabilizing the OF state. |
| HSt G796R (Iolascon et al., 2009) | In TM12 (dimerization) close to the transport-dimerization interface. Residue does not move in translocation, but substrate-binding site moves directly past G796. | Support. Arginine replacement of glycine in this position would be expected to impede elevator motion. |
| Mutation (reference) . | Location in the OF state and movement in the elevator mechanism . | Elevator mechanism: Support, refute, or neutral? . |
|---|---|---|
| HS C479W (Chu et al., 2010) found in compound heterozygote with dRTA mutation G701D | C479 is near extracellular end of TM3, facing TM4 and TM8. It moves inward with the transport domain in the translocation event. | Neutral. Tryptophan substitution could disrupt packing near the ends of TM4 and TM3, which could propagate to the binding site, but there are no major conformational changes here in the elevator mechanism. |
| HSt R730C, S731P (Bruce et al., 2005; Guizouarn et al., 2007; Stewart et al., 2011) | At the N-terminal end of TM10, near the substrate-binding site and expected to move with the substrate and the rest of the transport domain. | Neutral. Mutations at these sites would be expected to affect transport for almost any mechanism. |
| HSt H734R, S762R (Bruce et al., 2005) | These two residues are close to each other in the OF state. | Neutral. Arginine substitution is expected to disrupt packing in the transport domain. |
| HS D705Y (Bruce et al., 2005; Guizouarn et al., 2007; Barneaud-Rocca et al., 2013), | Near the cytoplasmic end of transport TM9, facing TM2 and nonhelical residues leading to TM3. | Neutral. Tyrosine substitution would interfere with packing within the transport domain. |
| HSt L687P (Bruce et al., 2005; Guizouarn et al., 2007; Stewart et al., 2011) | Cytoplasmic end of TM8 (transport), near Q521 of TM5 (dimerization) and V513, I516 of short helix H2. L687 moves several angstroms away from Q521, V513, and I516 in the translocation event. | Support. Proline for leucine would cause a bend near the end of TM8. Moreover, the smaller side chain would also likely have weaker interactions with H2, therefore destabilizing the OF state. |
| HSt G796R (Iolascon et al., 2009) | In TM12 (dimerization) close to the transport-dimerization interface. Residue does not move in translocation, but substrate-binding site moves directly past G796. | Support. Arginine replacement of glycine in this position would be expected to impede elevator motion. |
HS, hereditary spherocytosis; HSt, hereditary stomatocytosis.