Structural and functional analysis of critical amino acids in TMVI of the NHE1 isoform of the Na+/H+ exchanger

► Critical amino acids of TMVI of the Na+/H+ exchanger were mutated. ► TM VI critical residues include Asn227, Ile233, Leu243, Glu247 and Glu248. ► Mutant proteins yielded varying defects in activity expression and targeting. ► Modeling of TMVI indicates it forms a critical part of the ion conductance pathway.