Evolutionary mix-and-match with MFS transporters II

Significance The Major Facilitator Superfamily (MFS), the largest family of secondary transport proteins, catalyzes transport of a wide range of substrates. Difficulty discerning underlying mechanistic principles is due to low sequence conservation. However, a common structural feature of MFS members, suggesting that they may have arisen by intragenic multiplication, is a repeat of four three-helix bundles organized in two pseudosymmetrical domains. An alignment of these triple-helix motifs in combinatorial fashion allows detection of functionally homologous positions. Thus, substrate and H + -binding sites in distantly related symporters are located at the same relative positions. The structural organization also suggests that an ordered kinetic mechanism similar to that determined for lactose permease may be operative in other MFS symporters.