Evolutionary history of ATP‐binding cassette proteins

Abstract

ATP‐binding cassette (ABC) proteins are found in every sequenced genome and evolved deep in the phylogenetic tree of life. ABC proteins form one of the largest homologous protein families, with most being involved in substrate transport across biological membranes, and a few cytoplasmic members regulating in essential processes like translation. The predominant ABC protein classification scheme is derived from human members, but the increasing number of fully sequenced genomes permits to reevaluate this paradigm in the light of the evolutionary history the ABC‐protein superfamily. As we study the diversity of substrates, mechanisms, and physiological roles of ABC proteins, knowledge of the evolutionary relationships highlights similarities and differences that can be attributed to specific branches in protein divergence. While alignments and trees built on natural sequence variation account for the evolutionary divergence of ABC proteins, high‐throughput experiments and next‐generation sequencing creating experimental sequence variation are instrumental in identifying functional constraints. The combination of natural and experimentally produced sequence variation allows a broader and more rational study of the function and physiological roles of ABC proteins.

Multidrug Resistance in Mammals and Fungi—From MDR to PDR: A Rocky Road from Atomic Structures to Transport Mechanisms

“…The NBD dimerization compresses the central cavity space to drive substrate movement through the translocation, thus engaging a push and squeeze motion to open the valve. Substrates shift into the upper cavity and are released by the subsequent opening of the ECL lid (4). ATP hydrolysis at one NBD site may be enough to reset the catalytic cycle and to convert the transporter molecule into the inward-facing drug-recognizing state (5).…”

“…The ATP-binding cassette (ABC) transporter family is one of the largest protein superfamilies present in all living organisms, from prokaryotes to eukaryotes [ 1 , 2 , 3 , 4 , 5 ]. ABC transporters can operate as exporters or importers in an ATP-dependent manner, and mediate the membrane translocation of bewildering substrate spectra against concentration gradients [ 6 , 7 , 8 ].…”

“…Most ABC proteins from non-pathogenic baker’s yeasts ( Table 1 ) are also found in various numbers and functions in pathogenic fungi ( Table 2 ). A phylogenetic tree analysis suggests two major groups, referred to as exporter type I and type II [ 4 , 248 , 265 , 266 ], contain three MDR, MRP and PDR subfamilies ( Figure 1 A). While type I exporters (MDR/ABCB and MRP/ABCC) hold a TMD1­–NBD1–TMD2–NBD2 configuration, all PDR/ABCG type II exporters adopt a “reverse” architecture, such as NBD1–TMD1–NBD2–TMD2 ( Figure 1 B).…”

The incredible diversity of structures and functions of ABC transporters

“…Interestingly, this task turns out to be challenging, especially given the context of emerging new functional information, often in conflict with ‘established’ knowledge [32]. Here, genuine attempts to reclassify ABC transporters based on their TMD folds [33] or on evolutionary relationships obtained from the combination of natural and experimentally produced sequence variations are proposed [34,35]. Hopefully, this will stimulate debate, leading to the refinement of new proposals.…”

AlphaFold2 transmembrane protein structure prediction shines

“…The functional form of ABC proteins is built from two highly conservative nucleotide binding domains (NBDs) and two transmembrane domains (TMDs) which can be encoded in one or separate peptide chains. The low conservation of their TMDs are related to diverse functions and their currently known TM folds are also structurally divergent and can be classified into eight groups (Pgp-, ABCG2-, MalFG-, BtuC-, EcfT-, LptFG-, MacB-, and MlaElike folds) 13,14 . Our results demonstrate that AlphaFold2 provides reliable protein structures also for transmembrane proteins and can solve many issues associated with transmembrane protein structures.…”