Symmetry analysis and ancestral sequence reconstruction reveal a symmetrical translocation pathway and activity determinants of ZIP metal transporters

Short summary

Internal symmetry is broadly present across prokaryotic ZIP metal transporters, with reconstructed ancestral sequences showing even greater symmetry, supporting an evolutionary origin from a 4-transmembrane (TM) precursor via duplication and fusion. This symmetry framework reveals a continuous, symmetrical translocation pathway with distinct entry, transport, and exit sites and gates, enabling the identification of key residues (T529, V533) in the external gate of human ZIP4 that control metal transport.

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