期刊
NATURE COMMUNICATIONS
卷 7, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms12196
关键词
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资金
- Natural Sciences and Engineering Research Council of Canada
- National Research Council Canada
- Canadian Institutes of Health Research
- Province of Saskatchewan
- Western Economic Diversification Canada
- University of Saskatchewan
- Canada Research Chair
- Canadian Institutes of Health Research (CIHR) [MOP-133535]
- Austrian Academy of Sciences
- i-FIVE ERC grant
- CIHR Strategic Training Initiative in Chemical Biology
- CREATE Training Program in Bionanomachines (NSERC)
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.
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