7TDT
Cryo-EM structure of nanodisc-embedded human ABCA1
Summary for 7TDT
| Entry DOI | 10.2210/pdb7tdt/pdb |
| EMDB information | 25838 |
| Descriptor | Phospholipid-transporting ATPase ABCA1 (1 entity in total) |
| Functional Keywords | sterol transport, abc transporter, phospholipid transport, membrane protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 255391.80 |
| Authors | Plummer, A.M.,Culbertson, A.T.,Morales-Perez, C.L.,Liao, M. (deposition date: 2022-01-03, release date: 2023-03-29, Last modification date: 2024-11-06) |
| Primary citation | Plummer-Medeiros, A.M.,Culbertson, A.T.,Morales-Perez, C.L.,Liao, M. Activity and Structural Dynamics of Human ABCA1 in a Lipid Membrane. J.Mol.Biol., 435:168038-168038, 2023 Cited by PubMed Abstract: The human ATP-binding cassette (ABC) transporter ABCA1 plays a critical role in lipid homeostasis as it extracts sterols and phospholipids from the plasma membrane for excretion to the extracellular apolipoprotein A-I and subsequent formation of high-density lipoprotein (HDL) particles. Deleterious mutations of ABCA1 lead to sterol accumulation and are associated with atherosclerosis, poor cardiovascular outcomes, cancer, and Alzheimer's disease. The mechanism by which ABCA1 drives lipid movement is poorly understood, and a unified platform to produce active ABCA1 protein for both functional and structural studies has been missing. In this work, we established a stable expression system for both a human cell-based sterol export assay and protein purification for in vitro biochemical and structural studies. ABCA1 produced in this system was active in sterol export and displayed enhanced ATPase activity after reconstitution into a lipid bilayer. Our single-particle cryo-EM study of ABCA1 in nanodiscs showed protein induced membrane curvature, revealed multiple distinct conformations, and generated a structure of nanodisc-embedded ABCA1 at 4.0-Å resolution representing a previously unknown conformation. Comparison of different ABCA1 structures and molecular dynamics simulations demonstrates both concerted domain movements and conformational variations within each domain. Taken together, our platform for producing and characterizing ABCA1 in a lipid membrane enabled us to gain important mechanistic and structural insights and paves the way for investigating modulators that target the functions of ABCA1. PubMed: 36889459DOI: 10.1016/j.jmb.2023.168038 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (4 Å) |
Structure validation
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