PT - JOURNAL ARTICLE AU - Ieva Vasiliauskaité-Brooks AU - Robert D. Healey AU - Pascal Rochaix AU - Rémy Sounier AU - Claire Grison AU - Thierry Waltrich-Augusto AU - Mathieu Fortier AU - François Hoh AU - Essa M. Saied AU - Christoph Arenz AU - Shibom Basu AU - Cédric Leyrat AU - Sébastien Granier TI - Structure of a human intramembrane ceramidase explains enzymatic dysfunction found in leukodystrophy AID - 10.1101/348219 DP - 2018 Jan 01 TA - bioRxiv PG - 348219 4099 - http://biorxiv.org/content/early/2018/06/15/348219.short 4100 - http://biorxiv.org/content/early/2018/06/15/348219.full AB - 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.