Structural and functional diversity calls for a new classification of ABC transporters

Abstract

Members of the ATP‐binding cassette (ABC) transporter superfamily translocate a broad spectrum of chemically diverse substrates. While their eponymous ATP‐binding cassette in the nucleotide‐binding domains (NBDs) is highly conserved, their transmembrane domains (TMDs) forming the translocation pathway exhibit distinct folds and topologies, suggesting that during evolution the ancient motor domains were combined with different transmembrane mechanical systems to orchestrate a variety of cellular processes. In recent years, it has become increasingly evident that the distinct TMD folds are best suited to categorize the multitude of ABC transporters. We therefore propose a new ABC transporter classification that is based on structural homology in the TMDs.

Structure of bacterial phospholipid transporter MlaFEDB with substrate bound

“…Despite negligible sequence similarity, the core MlaE fold is related to the TMDs of several other ABC transporters. MlaE most closely resembles the LPS exporter LptF/LptG ( Thomas et al, 2020 ) and the macrolide antibiotic efflux pump MacB ( Crow et al, 2017 ; Fitzpatrick et al, 2017 ; Okada et al, 2017 ; Figure 2B–J ), but also shares similarities with the glycolipid flippases Wzm ( Bi et al, 2018 ; Caffalette et al, 2019 ) and TarG ( Chen et al, 2020 ) and the eukaryotic ABCA/ABCG families ( Figure 2—figure supplement 1 ). However, MlaE also displays notable differences.…”

Capturing the interplay of membrane lipids and structural transitions in human ABCA7

“…To establish whether the rigid body motions outlined above extend to other ABC transporters of the Type-V fold (Thomas et al, 2020), we extended our analysis of individual TMD-NBD pairs to members of the G family for which structural data is available, namely ABCG2 and ABCG5/G8 ( Figure 6A). As shown in Figure 6B, TMD-NBD pairs from both the apo open (Orlando and Liao, 2020) and ATP bound closed conformation of ABCG2 (Manolaridis et al, 2018) share a virtually .…”

In vitro reconstitution of dynamically interacting integral membrane subunits of energy-coupling factor transporters

“…In prokaryotes three major classes of ABC transporters involved in import have been distinguished based on the fold of the transmembrane domains. In two of these classes (named Type I and Type II ABC transporters) ( Thomas et al, 2020 ), extracellular or periplasmic proteins are required for substrate binding and delivery to the transporter, called substrate-binding proteins or domains (SBPs or SBDs).…”