Title : Structural Basis for Nucleotide Hydrolysis by the
Acid Sphingomyelinase-like
Phosphodiesterase SMPDL3A
Abstract :
- Sphingomyelin phosphodiesterase, acid-like 3A ( SMPDL3A ) is a member of a small family of proteins founded by the well characterized lysosomal enzyme , acid sphingomyelinase ( ASMase )
- ASMase converts sphingomyelin into the signaling lipid, ceramide
- It was recently discovered that, in contrast to ASMase , SMPDL3A is inactive against sphingomyelin and, surprisingly, can instead hydrolyze nucleoside diphosphates and triphosphates, which may play a role in purinergic signaling
- As none of the ASMase-like proteins has been structurally characterized to date, the molecular basis for their substrate preferences is unknown
- Here we report crystal structures of murine SMPDL3A , which represent the first structures of an ASMase-like protein
- The catalytic domain consists of a central mixed β-sandwich surrounded by α-helices
- Additionally, SMPDL3A possesses a unique C-terminal domain formed from a cluster of four α-helices that appears to distinguish this protein family from other phosphoesterases
- We show that SMDPL3A is a di-zinc-dependent enzyme with an active site configuration that suggests a mechanism of phosphodiester hydrolysis by a metal-activated water molecule and protonation of the leaving group by a histidine residue
- Co-crystal structures of SMPDL3A with AMP and α,β-methylene ADP (AMPCP) reveal that the substrate binding site accommodates nucleotides by establishing interactions with their base, sugar, and phosphate moieties, with the latter the major contributor to binding affinity
- Our study provides the structural basis for SMPDL3A substrate specificity and sheds new light on the function of ASMase-like proteins
Output (sent_index, trigger,
protein,
sugar,
site):
Output(Part-Of) (sent_index,
protein,
site):
- 7. Additionally, SMPDL3A, domain
*Output_Site_Fusion* (sent_index,
protein,
sugar,
site):