Crystal structure of the human sterol transporter ABCG5/ABCG8

Abstract

ATP binding cassette (ABC) transporters play critical roles in maintaining sterol balance in higher eukaryotes. The ABCG5/ABCG8 heterodimer (G5G8) mediates excretion of neutral sterols in liver and intestines1–5. Mutations disrupting G5G8 cause sitosterolaemia, a disorder characterized by sterol accumulation and premature atherosclerosis. Here we use crystallization in lipid bilayers to determine the X-ray structure of human G5G8 in a nucleotide-free state at 3.9 Å resolution, generating the first atomic model of an ABC sterol transporter. The structure reveals a new transmembrane fold that is present in a large and functionally diverse superfamily of ABC transporters. The transmembrane domains are coupled to the nucleotide-binding sites by networks of interactions that differ between the active and inactive ATPases, reflecting the catalytic asymmetry of the transporter. The G5G8 structure provides a mechanistic framework for understanding sterol transport and the disruptive effects of mutations causing sitosterolaemia.

Architectures of Lipid Transport Systems for the Bacterial Outer Membrane

“…These residues lie at the predicted cytoplasmic end of MlaE and on the surface of MlaF employed by other ABC ATPases to interact with their permease subunits (Figure S3D), supporting the placement and orientation of the Mla subunits in our cryo-EM map. Strikingly, this predicted model of the MlaE permease subunit closely resembles the overall fold of ABCG5/ABCG8 (Figure S3E), a recently determined human ABC transporter structure involved in cholesterol export from hepatocytes (Lee et al, 2016). While the structure of MlaE remains to be determined experimentally, true homology with ABCG5/ABCG8 would group MCE transporters with this important class of ABCG transporters exporting another hydrophobic substrate, cholesterol, in humans.…”

Structural basis for antibacterial peptide self‐immunity by the bacterial ABC transporter McjD

“…The NBDs have moved in a “scissors‐like” motion similar to the transition between inward and outward‐open MsbA. A small degree of disengagement between the NBDs has also been reported for the heterodimeric ABC exporter TM287/288 (Hohl et al , 2012; Hohl et al , 2014), ABCG5/8 (Lee et al , 2016) and LptB 2 FG (Luo et al , 2017). …”

“…The McjD‐apo structure can be superimposed with the McjD‐AMPPNP structure with an rmsd of 2.1 Å over 569 Cα atoms; their TMDs can be superimposed with an rmsd of 0.7 Å over 290 Cα atoms. The heterodimeric human sterol apo‐ABCG5/8 (Lee et al , 2016) and Pseudomonas aeruginosa lipopolysaccharide apo‐LptB 2 FG (Luo et al , 2017) do not display intertwining either.…”

A structure-activity relationship study of ABCC2 inhibitors

“…The structure of ABCC2 is not yet known, but the crystal structures of related mammalian ABC transporters have been reported (Aller et al 2009, Lee et al 2016). A common feature of these transporters is a large cavity formed within their transmembrane domains, which is likely to contain the substrate binding site (Aller et al 2009).…”