Key result
Mutations in the intracellular region connecting TM8 and TM9 of AE1, specifically at Lys-695 and Lys-698, abolish anion exchange and induce a cation leak, indicating the same transport pathway mediates both functions.
This preclinical study demonstrates that specific point mutations in human anion exchanger 1 (AE1) can convert it from an obligate anion exchanger into a cation channel using the same transmembrane pathway.
AE1 mutations may induce cation leak via the anion pathway in models; leaves open therapeutic targeting in human red cell disorders.
Previous results suggested that specific point mutations in human anion exchanger 1 (AE1) convert the electroneutral anion exchanger into a monovalent cation conductance. In the present study, the transport site for anion exchange and for the cation leak has been studied by cysteine scanning mutagenesis and sulfhydryl reagent chemistry. Moreover, the role of some highly conserved amino acids within members of the SLC4 family to which AE1 belongs has been assessed in AE1 transport properties. The results suggest that the same transport site within the AE1 spanning domain is involved in anion exchange or in cation transport. A functioning mechanism for this transport site is proposed according to transport properties of the different studied point mutations of AE1.
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Barneaud-Rocca et al. (2011) studied this question. Site-directed mutagenesis of AE1 vs. Wild-type AE1 was evaluated on Cl-/HCO3- exchange activity and Li+ uptake. Mutations in the intracellular region connecting TM8 and TM9 of AE1, specifically at Lys-695 and Lys-698, abolish anion exchange and induce a cation leak, indicating the same transport pathway mediates both functions.
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