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