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.

journal_name

Nat Commun

journal_title

Nature communications

authors

Gorelik A,Illes K,Heinz LX,Superti-Furga G,Nagar B

doi

10.1038/ncomms12196

subject

Has Abstract

pub_date

2016-07-20 00:00:00

pages

12196

issn

2041-1723

pii

ncomms12196

journal_volume

7

pub_type

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