*2.3. ABCA7 Structure*

Functional ABC transporters are commonly composed of four domains—two transmembrane domains (TMDs) connected with two cytoplasmic nucleotide-binding domains (NBDs). TMDs are variable in sequence and are responsible for substrate interaction and translocation. NBDs are highly conserved and have characteristic motifs such as Walker A and Walker B, allowing to bind and hydrolyze ATP. As shown in Figure 2, full ABC transporters like transporters of subfamilies A and C have 2 TMDs. ABC transporters of the D and G subfamilies such as ABCG1 or ABCG2 display only one TMD and one NBD. They are therefore considered as half-transporters and have to homo- or hetero-dimerize to be functional. ABC transporters are classified based on their NBD domain but it was recently suggested that it would be more pertinent to use a TMD-based classification system [1].

**Figure 2.** Schematic representation of the full ABC transporters of the subfamily A. Two transmembrane domains (TMDs) are connected with two cytoplasmic nucleotide-binding domains (NBDs). In addition, members of subfamily A are characterized by two large extracellular domains (ECD1 and ECD2). Reprinted from [26] with permission from Elsevier.

ABCA7 is predicted to be a full ABC transporter, as presented in Figure 2. The transport mechanism of these transporters is controlled by alternating the conformation of TMD, through which the transporter switches between inward- and outward-facing states. Recently, alternative mechanisms have been proposed or identified, suggesting that this process remains under debate [27]. In all cases, the exact transport mechanism of ABCA7 is uncharacterized, and, despite the fact that single-particle cryoelectron microscopy (cryo-EM) structure of ABCA1 has been recently obtained [28], the structure of ABCA7 is still unknown.

Sequence comparisons made with other ABC transporters showed high ABCA7 homology with ABCA1 (54%), ABCA2 (45%), ABCA3 (41%) and ABCA4 (49%) [11]. Because these latter are involved in lipid transport, it was rapidly assumed that ABCA7 was also able to transfer lipid from cell membranes to lipoproteins.
