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Structure of a human intramembrane ceramidase explains enzymatic dysfunction found in leukodystrophy

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  • Ieva Vasiliauskaité-Brooks

    (IGF, University of Montpellier, CNRS, INSERM)

  • Robert D. Healey

    (IGF, University of Montpellier, CNRS, INSERM)

  • Pascal Rochaix

    (IGF, University of Montpellier, CNRS, INSERM)

  • Julie Saint-Paul

    (IGF, University of Montpellier, CNRS, INSERM)

  • Rémy Sounier

    (IGF, University of Montpellier, CNRS, INSERM)

  • Claire Grison

    (IGF, University of Montpellier, CNRS, INSERM)

  • Thierry Waltrich-Augusto

    (IGF, University of Montpellier, CNRS, INSERM)

  • Mathieu Fortier

    (IGF, University of Montpellier, CNRS, INSERM)

  • François Hoh

    (CBS, University of Montpellier, CNRS, INSERM)

  • Essa M. Saied

    (Humboldt-Universität zu Berlin
    Suez Canal University)

  • Christoph Arenz

    (Humboldt-Universität zu Berlin)

  • Shibom Basu

    (Paul Scherrer Institut)

  • Cédric Leyrat

    (IGF, University of Montpellier, CNRS, INSERM)

  • Sébastien Granier

    (IGF, University of Montpellier, CNRS, INSERM)

Abstract

Alkaline ceramidases (ACERs) are a class of poorly understood transmembrane enzymes controlling the homeostasis of ceramides. They are implicated in human pathophysiology, including progressive leukodystrophy, colon cancer as well as acute myeloid leukemia. We report here the crystal structure of the human ACER type 3 (ACER3). Together with computational studies, the structure reveals that ACER3 is an intramembrane enzyme with a seven transmembrane domain architecture and a catalytic Zn2+ binding site in its core, similar to adiponectin receptors. Interestingly, we uncover a Ca2+ binding site physically and functionally connected to the Zn2+ providing a structural explanation for the known regulatory role of Ca2+ on ACER3 enzymatic activity and for the loss of function in E33G-ACER3 mutant found in leukodystrophic patients.

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  • Ieva Vasiliauskaité-Brooks & Robert D. Healey & Pascal Rochaix & Julie Saint-Paul & Rémy Sounier & Claire Grison & Thierry Waltrich-Augusto & Mathieu Fortier & François Hoh & Essa M. Saied & Christoph, 2018. "Structure of a human intramembrane ceramidase explains enzymatic dysfunction found in leukodystrophy," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07864-w
    DOI: 10.1038/s41467-018-07864-w
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    Cited by:

    1. Dandan Qian & Ye Cong & Runhao Wang & Quan Chen & Chuangye Yan & Deshun Gong, 2023. "Structural insight into the human SID1 transmembrane family member 2 reveals its lipid hydrolytic activity," Nature Communications, Nature, vol. 14(1), pages 1-10, December.

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