Consistency between the proposed elevator-like mechanism and known disease-related mutations. (A and B) SAO deletion of residues 400–409 (magenta) in H1/TM1 would cause loss of interactions to TM7 and TM10 found in the OF state (A) but not present in the predicted IF state (B). (A) The AE1 structure (PDB ID 4YZF) is viewed along the plane of the membrane, with the cytoplasm at the bottom (left), or from the extracellular side (right). (B) The repeat-swapped model of AE1 is viewed along the plane of the membrane. (C) Mutations at positions interacting with H2. P868 (yellow) of TM14 is mutated to P868L in the high-transport (HT) variant, and L687 (magenta) of TM8 is mutated to L687P in hereditary stomatocytosis (HSt). P868 is predicted to form closer contacts with L516 in the H2 linker in the IF repeat-swapped model due to the reorientation of the transport domain relative to the dimerization domain. In contrast, L687 forms contacts with I516 and V513 of H2 and Q521 of TM5 in the OF conformation that are predicted to be lost in the IF state.