UC San Diego

ATP-binding Cassette (ABC) transporters use ATP as an energy source and move a variety of substrates concentratively across cellular membranes. Previous studies based on primary protein sequence data suggested that integral membrane ABC exporters evolved independently at least three times, giving rise to three ABC types. Given the increasing availability of ABC structures in the Protein Data Bank (PDB) and the substantially larger number of primary sequences, we could investigate whether the current data support the conclusions obtained based on sequence analyses alone. We conducted sequence and structural analyses on the transmembrane domains (TMDs) and the nucleotide binding (ATPase) domains (NBDs) of the three proposed ABC types, ABC1 in which a repeat unit of 2 TMSs triplicated, ABC2 in which a repeat unit of 3 TMSs duplicated, and ABC3 in which a repeat unit of 4 TMSs duplicated. The three most divergent families of the 70 ABC exporter families were excluded from our studies. The clustering patterns of both the TMDs and the NBDs showed that ABC1 forms a monophyletic group, whereas ABC2 and ABC3 share a major branch. The topological similarities of the two trees for the TMDs and NBDs strongly support the notion that these two domains have co-evolved. Based on sequence and structural divergence as well as organismal distribution, we suggest that ABC2s evolved first, followed by ABC1, and then ABC3. Our results provide insight into the evolutionary relationships between ABC types and serve as a guide for future studies of the ABC superfamily.