Functional hotspots revealed by mutational, evolutionary, and structural characterization of ABC transporters
Membrane proteins serve as cellular gatekeepers, regulators, and sensors. Some examples of large membrane protein families with prominent roles in human health include ATP-binding cassette transporters (ABC) that protect cells from external toxins, G-protein coupled receptors that respond to extracellular signals, and voltage-sensing ion channels. Despite their importance for normal cellular function, less than 1% of the structures in the Protein Data Bank (PDB) are high-resolution structures of membrane-bound proteins, providing only sparse data for structure-based functional annotation. In the absence of structure, mechanistic insight into membrane protein function is lacking. In contrast, sequence databases are growing rapidly and include large numbers of uncharacterized genetic variants found in the human genome. Here, I use computational methods to improve functional annotation of point mutations in human membrane proteins, focusing on a large and diverse group of membrane transporters, the ABC transporter superfamily.