Title : Structural basis for the activation of
acid ceramidase
Abstract :
- Acid ceramidase ( aCDase , ASAH1 ) hydrolyzes lysosomal membrane ceramide into sphingosine, the backbone of all sphingolipids, to regulate many cellular processes
- Abnormal function of aCDase leads to Farber disease, spinal muscular atrophy with progressive myoclonic epilepsy, and is associated with Alzheimer's, diabetes, and cancer
- Here, we present crystal structures of mammalian aCDases in both proenzyme and autocleaved forms
- In the proenzyme , the catalytic center is buried and protected from solvent
- Autocleavage triggers a conformational change exposing a hydrophobic channel leading to the active site
- Substrate modeling suggests distinct catalytic mechanisms for substrate hydrolysis versus autocleavage
- A hydrophobic surface surrounding the substrate binding channel appears to be a site of membrane attachment where the enzyme accepts substrates facilitated by the accessory protein , saposin-D
- Structural mapping of disease mutations reveals that most would destabilize the protein fold
- These results will inform the rational design of aCDase inhibitors and recombinant aCDase for disease therapeutics
Output (sent_index, trigger,
protein,
sugar,
site):
Output(Part-Of) (sent_index,
protein,
site):
*Output_Site_Fusion* (sent_index,
protein,
sugar,
site):