8k7c | pdb_00008k7c
Outward-facing structure of human ABCB6 W546A mutant (ADP/VO4-bound)
Structural highlights
DiseaseABCB6_HUMAN Ocular coloboma;Dyschromatosis universalis;Colobomatous microphthalmia. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. ABCB6 mutations are involved in familial pseudohyperkalemia, a dominantly inherited condition characterized by increased serum potassium levels, measured in whole-blood specimens stored at or below room temperature. This condition is not accompanied by clinical symptoms or biological signs except for borderline abnormalities of red cell shape (PubMed:23180570).[1] FunctionABCB6_HUMAN Binds heme and porphyrins and functions in their ATP-dependent uptake into the mitochondria. Plays a crucial role in heme synthesis.[2] [3] Publication Abstract from PubMedHuman ATP-binding cassette transporter subfamily B6 (ABCB6) is a mitochondrial ATP-driven pump that translocates porphyrins from the cytoplasm into mitochondria for heme biosynthesis. Within the transport pathway, a conserved aromatic residue W546 located in each monomer plays a pivotal role in stabilizing the occluded conformation via pi-stacking interactions. Herein, we employed cryo-electron microscopy to investigate the structural consequences of a single W546A mutation in ABCB6, both in detergent micelles and nanodiscs. The results demonstrate that the W546A mutation alters the conformational dynamics of detergent-purified ABCB6, leading to entrapment of the transporter in an outward-facing transient state. However, in the nanodisc system, we observed a direct interaction between the transporter and a phospholipid molecule that compensates for the absence of the W546 residue, thereby facilitating the normal conformational transition of the transporter toward the occluded state following ATP hydrolysis. The findings also reveal that adoption of the outward-facing conformation causes charge repulsion between ABCB6 and the bound substrate, and rearrangement of key interacting residues at the substrate-binding site. Consequently, the affinity for the substrate is significantly reduced, facilitating its release from the transporter. W546 stacking disruption traps the human porphyrin transporter ABCB6 in an outward-facing transient state.,Lee SS, Park JG, Jang E, Choi SH, Kim S, Kim JW, Jin MS Commun Biol. 2023 Sep 21;6(1):960. doi: 10.1038/s42003-023-05339-3. PMID:37735522[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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