Cryo-EM structure of lipid embedded human ABCA7 at 3.6Å resolution

Abstract

AbstractDysfunction of the ATP Binding Cassette (ABC) transporter ABCA7 alters cellular lipid homeostasis and is linked to Alzheimer’s Disease (AD) pathogenesis through poorly understood mechanisms. Here we determined the cryo-electron microscopy (cryo-EM) structure of human ABCA7 in a lipid environment at 3.6Å resolution that reveals an open conformation, despite bound nucleotides, and bilayer lipids traversing the transmembrane domain (TMD). We show that ATP hydrolysis in ABCA7 is modulated by its lipid environment as well as apolipoprotein (apo) A1 and apoE, the latter in an isoform dependent manner, and that apoA1 can directly bind ABCA7. Structural similarities between ABCA and ABCG family transporters suggest that TMD-nucleotide binding domain (NBD) pairs in both sets move as single rigid bodies to affect conformational transitions. Our data suggest these transitions in ABCA7 are influenced by TMD cavity lipids and apolipoprotein binding in addition to being coupled to ATP hydrolysis.