Structural Insights into Porphyrin Recognition by the Human ATP-Binding Cassette Transporter ABCB6

Human ABCB6 is an ATP-binding cassette transporter that regulates heme biosynthesis by translocating various porphyrins from the cytoplasm into the mitochondria. Here we report the cryo-electron microscopy (cryo-EM) structures of human ABCB6 with its substrates, coproporphyrin III (CPIII) and hemin,...

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Bibliographic Details
Published in:Molecules and cells 2022, 45(8), , pp.575-587
Main Authors: Kim, Songwon, Lee, Sang Soo, Park, Jun Gyou, Kim, Ji Won, Ju, Seulgi, Choi, Seung Hun, Kim, Subin, Kim, Na Jin, Hong, Semi, Kang, Jin Young, Jin, Mi Sun
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - metabolism
ATP-Binding Cassette Transporters - metabolism
Cryoelectron Microscopy
Glutathione - metabolism
Hemin - metabolism
Humans
Porphyrins - metabolism
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Summary:Human ABCB6 is an ATP-binding cassette transporter that regulates heme biosynthesis by translocating various porphyrins from the cytoplasm into the mitochondria. Here we report the cryo-electron microscopy (cryo-EM) structures of human ABCB6 with its substrates, coproporphyrin III (CPIII) and hemin, at 3.5 and 3.7 Å resolution, respectively. Metalfree porphyrin CPIII binds to ABCB6 within the central cavity, where its propionic acids form hydrogen bonds with the highly conserved Y550. The resulting structure has an overall fold similar to the inward-facing apo structure, but the two nucleotide-binding domains (NBDs) are slightly closer to each other. In contrast, when ABCB6 binds a metal-centered porphyrin hemin in complex with two glutathione molecules (1 hemin: 2 glutathione), the two NBDs end up much closer together, aligning them to bind and hydrolyze ATP more efficiently. In our structures, a glycine-rich and highly flexible "bulge" loop on TM helix 7 undergoes significant conformational changes associated with substrate binding. Our findings suggest that ABCB6 utilizes at least two distinct mechanisms to fine-tune substrate specificity and transport efficiency.
ISSN:1016-8478
0219-1032
DOI:10.14348/molcells.2022.0040