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Cryo-EM structures of the ABCA4 importer reveal mechanisms underlying substrate binding and Stargardt disease

Author

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  • Jessica Fernandes Scortecci

    (University of British Columbia)

  • Laurie L. Molday

    (University of British Columbia)

  • Susan B. Curtis

    (University of British Columbia)

  • Fabian A. Garces

    (University of British Columbia)

  • Pankaj Panwar

    (University of British Columbia)

  • Filip Petegem

    (University of British Columbia)

  • Robert S. Molday

    (University of British Columbia
    University of British Columbia)

Abstract

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.

Suggested Citation

  • Jessica Fernandes Scortecci & Laurie L. Molday & Susan B. Curtis & Fabian A. Garces & Pankaj Panwar & Filip Petegem & Robert S. Molday, 2021. "Cryo-EM structures of the ABCA4 importer reveal mechanisms underlying substrate binding and Stargardt disease," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26161-7
    DOI: 10.1038/s41467-021-26161-7
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    References listed on IDEAS

    as
    1. Faraz Quazi & Stepan Lenevich & Robert S. Molday, 2012. "ABCA4 is an N-retinylidene-phosphatidylethanolamine and phosphatidylethanolamine importer," Nature Communications, Nature, vol. 3(1), pages 1-9, January.
    2. Jyh-Yeuan Lee & Lisa N. Kinch & Dominika M. Borek & Jin Wang & Junmei Wang & Ina L. Urbatsch & Xiao-Song Xie & Nikolai V. Grishin & Jonathan C. Cohen & Zbyszek Otwinowski & Helen H. Hobbs & Daniel M. , 2016. "Crystal structure of the human sterol transporter ABCG5/ABCG8," Nature, Nature, vol. 533(7604), pages 561-564, May.
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    Cited by:

    1. Thibaud Dieudonné & Felix Kümmerer & Michelle Juknaviciute Laursen & Charlott Stock & Rasmus Kock Flygaard & Syma Khalid & Guillaume Lenoir & Joseph A. Lyons & Kresten Lindorff-Larsen & Poul Nissen, 2023. "Activation and substrate specificity of the human P4-ATPase ATP8B1," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Zhi-Peng Chen & Da Xu & Liang Wang & Yao-Xu Mao & Yang Li & Meng-Ting Cheng & Cong-Zhao Zhou & Wen-Tao Hou & Yuxing Chen, 2022. "Structural basis of substrate recognition and translocation by human very long-chain fatty acid transporter ABCD1," Nature Communications, Nature, vol. 13(1), pages 1-10, December.

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