| First Author | Gorelik A | Year | 2016 |
| Journal | Nat Commun | Volume | 7 |
| Pages | 12196 | PubMed ID | 27435900 |
| Mgi Jnum | J:241171 | Mgi Id | MGI:5897945 |
| Doi | 10.1038/ncomms12196 | Citation | Gorelik A, et al. (2016) Crystal structure of mammalian acid sphingomyelinase. Nat Commun 7:12196 |
| abstractText | 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. |
