IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v12y2021i1d10.1038_s41467-021-26161-7.html
   My bibliography  Save this article

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

Author

Listed:
  • 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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-021-26161-7
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-021-26161-7?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    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.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    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.

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Alejandro Marín-Medina & Gonzalo Ruíz-Hidalgo & Jorge L. Blé-Castillo & Alma M. Zetina-Esquivel & Rodrigo Miranda Zamora & Isela E. Juárez-Rojop & Juan C. Díaz-Zagoya, 2019. "Combined Effect of Diosgenin Along with Ezetimibe or Atorvastatin on the Fate of Labelled Bile Acid and Cholesterol in Hypercholesterolemic Rats," IJERPH, MDPI, vol. 16(4), pages 1-10, February.
    2. Jere P. Segrest & Chongren Tang & Hyun D. Song & Martin K. Jones & W. Sean Davidson & Stephen G. Aller & Jay W. Heinecke, 2022. "ABCA1 is an extracellular phospholipid translocase," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    3. Young Jin Kim & Sanghoon Moon & Mi Yeong Hwang & Sohee Han & Hye-Mi Jang & Jinhwa Kong & Dong Mun Shin & Kyungheon Yoon & Sung Min Kim & Jong-Eun Lee & Anubha Mahajan & Hyun-Young Park & Mark I. McCar, 2022. "The contribution of common and rare genetic variants to variation in metabolic traits in 288,137 East Asians," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26161-7. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.