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-Structure paper
タイトル | Cryo-EM structures of the ABCA4 importer reveal mechanisms underlying substrate binding and Stargardt disease. |
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ジャーナル・号・ページ | Nat Commun, Vol. 12, Issue 1, Page 5902, Year 2021 |
掲載日 | 2021年10月8日 |
著者 | Jessica Fernandes Scortecci / Laurie L Molday / Susan B Curtis / Fabian A Garces / Pankaj Panwar / Filip Van Petegem / Robert S Molday / |
PubMed 要旨 | ABCA4 is an ATP-binding cassette (ABC) transporter that flips N-retinylidene-phosphatidylethanolamine (N-Ret-PE) from the lumen to the cytoplasmic leaflet of photoreceptor membranes. Loss-of-function ...ABCA4 is an ATP-binding cassette (ABC) transporter that flips N-retinylidene-phosphatidylethanolamine (N-Ret-PE) from the lumen to the cytoplasmic leaflet of photoreceptor membranes. Loss-of-function mutations cause Stargardt disease (STGD1), a macular dystrophy associated with severe vision loss. To define the mechanisms underlying substrate binding and STGD1, we determine the cryo-EM structure of ABCA4 in its substrate-free and bound states. The two structures are similar and delineate an elongated protein with the two transmembrane domains (TMD) forming an outward facing conformation, extended and twisted exocytoplasmic domains (ECD), and closely opposed nucleotide binding domains. N-Ret-PE is wedged between the two TMDs and a loop from ECD1 within the lumen leaflet consistent with a lateral access mechanism and is stabilized through hydrophobic and ionic interactions with residues from the TMDs and ECDs. Our studies provide a framework for further elucidating the molecular mechanism associated with lipid transport and disease and developing promising disease interventions. |
リンク | Nat Commun / PubMed:34625547 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 2.92 - 3.6 Å |
構造データ | EMDB-23617, PDB-7m1p: EMDB-23618, PDB-7m1q: |
化合物 | ChemComp-NAG: ChemComp-HOH: ChemComp-HZL: ChemComp-MG: |
由来 |
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キーワード | TRANSPORT PROTEIN / ABC transporter / importer / MEMBRANE PROTEIN |