Crystal structure of mammalian acid sphingomyelinase

Nat Commun. 2016 Jul 20:7:12196. doi: 10.1038/ncomms12196.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Catalytic Domain
  • Crystallography, X-Ray
  • Enzyme Assays
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism
  • Humans
  • Hydrolysis
  • Mammals / metabolism*
  • Membrane Lipids / metabolism
  • Mice
  • Models, Molecular
  • Molecular Docking Simulation
  • Mutation / genetics
  • Niemann-Pick Diseases / genetics
  • Protein Structure, Secondary
  • Saposins / chemistry
  • Sphingomyelin Phosphodiesterase / chemistry*
  • Sphingomyelin Phosphodiesterase / genetics
  • Sphingomyelin Phosphodiesterase / isolation & purification
  • Sphingomyelin Phosphodiesterase / metabolism
  • Static Electricity
  • Substrate Specificity


  • Enzyme Inhibitors
  • Membrane Lipids
  • Saposins
  • Sphingomyelin Phosphodiesterase