Molecular mechanisms of intramembrane ceramidases revealed by structural biology

Dr Robert D. Healey
IGF, University of Montpellier, CNRS, INSERM, Montpellier, France
3 May 2019 - 3:00pm
Rountree Room 356, Level 3, Biological Sciences Building D26

This seminar will explore the molecular mechanisms of ceramide hydrolysis by intramembrane ceramidases. Ceramidases modulate levels of ceramide and sphingosine: bioactive lipids implicated in a diverse range of cellular functions. Using membrane protein X-ray crystallography, the atomic structures of a new family of receptors (the progestin and adipoQ receptors (PAQR)) were elucidated and an intrinsic ceramidase enzymatic activity was discovered1. Furthermore, the atomic structure of a putative ceramidase enzyme, alkaline ceramidase 3 (ACER3) was also solved2. An ACER3 mutation (E33G) has been described leading to the development of leukodystrophy, and the enzymatic activity has been linked to colon cancer and acute myeloid leukemia. By combining structural studies with biochemical assays and molecular dynamic simulations, the molecular mechanism causing leukodystrophy has now been elucidated.

This seminar will also highlight some of the technical challenges to be overcome when working with purified membrane proteins for integrated structural biology approaches.  

1. Vasiliauskaité-Brooks, I. and Sounier, R., et al. Structural insights into adiponectin receptors suggest ceramidase activity. Nature. 544, 120 (2017).

2. Vasiliauskaité-Brooks I. and Healey R.D., et al. Structure of a human intramembrane ceramidase explains enzymatic dysfunction found in leukodystrophy. Nat. Comm. 9, 5437 (2018).

Speaker BiographyRobert D. Healey is a postdoc at the Institut de Génomique Fonctionnelle (IGF) in sunny Montpellier, France. He received his PhD in Chemistry from UNSW in 2017. His PhD thesis focused on understanding how sweet tasting proteins interact with G protein-coupled receptors in the mouth.