Journal
MOLECULES AND CELLS
Volume 45, Issue 8, Pages 575-587Publisher
KOREAN SOC MOLECULAR & CELLULAR BIOLOGY
Keywords
ABCB6; ATP-binding cassette transporter; cryoelectron microscopy; glutathione; porphyrin
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Funding
- National Research Foundation (NRF) - Ministry of Science, ICT, and Future Planning of Korea (MSIP) [NRF2017M3A9F6029753, NRF-2019M3E5D6066058, NRF-2019R1A6A1A10073887, NRF-2021M3A9I4022846]
- GIST Research Institute (GRI) IIBR - GIST
- NRF - MSIP [NRF-2020R1I1A1A01072077]
- National Research Foundation of Korea [2021M3A9I4022846] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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The cryo-EM structures of human ABCB6 with its substrates CPIII and hemin were reported. The study revealed that ABCB6 utilizes different mechanisms to regulate substrate specificity and transport efficiency.
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 A 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.
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