title: Crystal structure of mammalian acid sphingomyelinase.
abstract: Acid sphingomyelinase (ASMase, ASM, SMPD1) converts sphingomyelin into ceramide, modulating membrane properties and signal transduction. Inactivating mutations in ASMase cause Niemann-Pick disease, and its inhibition is also beneficial in models of depression and cancer. To gain a better understanding of this critical therapeutic target, we determined crystal structures of mammalian ASMase in various conformations. The catalytic domain adopts a calcineurin-like fold with two zinc ions and a hydrophobic track leading to the active site. Strikingly, the membrane interacting saposin domain assumes either a closed globular conformation independent from the catalytic domain, or an open conformation, which establishes an interface with the catalytic domain essential for activity. Structural mapping of Niemann-Pick mutations reveals that most of them likely destabilize the protein's fold. This study sheds light on the molecular mechanism of ASMase function, and provides a platform for the rational development of ASMase inhibitors and therapeutic use of recombinant ASMase.
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Quebec, Canada H3G 0B1.|Groupe de Recherche Axé sur la Structure des Protéines, McGill University, Montreal, Quebec, Canada H3G 0B1.
authors.forename: Alexei
authors.initials: A
authors.lastname: Gorelik
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Quebec, Canada H3G 0B1.|Groupe de Recherche Axé sur la Structure des Protéines, McGill University, Montreal, Quebec, Canada H3G 0B1.
authors.forename: Katalin
authors.initials: K
authors.lastname: Illes
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.|Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Leonhard X
authors.initials: LX
authors.lastname: Heinz
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.|Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Giulio
authors.initials: G
authors.lastname: Superti-Furga
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Quebec, Canada H3G 0B1.|Groupe de Recherche Axé sur la Structure des Protéines, McGill University, Montreal, Quebec, Canada H3G 0B1.
authors.forename: Bhushan
authors.initials: B
authors.lastname: Nagar
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D057075:Enzyme Assays; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D008322:Mammals / Q000378:metabolism*; D008563:Membrane Lipids / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009154:Mutation / Q000235:genetics; D009542:Niemann-Pick Diseases / Q000235:genetics; D017433:Protein Structure, Secondary; D049231:Saposins / Q000737:chemistry; D013108:Sphingomyelin Phosphodiesterase / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D055672:Static Electricity; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D008563:Membrane Lipids; D049231:Saposins; D013108:Sphingomyelin Phosphodiesterase