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

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 Arenz, Shibom Basu, Cédric Leyrat () and Sébastien Granier ()
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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
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

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07864-w

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