Title : Crystal
structure of the Acid Sphingomyelinase-like
Phosphodiesterase SMPDL3B Provides Insights into Determinants of Substrate Specificity
Abstract :
- The enzyme acid sphingomyelinase-like phosphodiesterase 3B ( SMPDL3B ) was shown to act as a negative regulator of innate immune signaling, affecting cellular lipid com position and membrane fluidity
- Furthermore, several reports identified this enzyme as an off target of the therapeutic antibody rituximab, with implications in kidney disorders
- However, structural information for this protein is lacking
- Here we present the high resolution crystal structure of murine SMPDL3B , which reveals a substrate binding site strikingly different from its paralogs
- The active site is located in a narrow boot-shaped cavity
- We identify a unique loop near the active site that appears to impose size constraints on incoming substrates
- A structure in complex with phosphocholine indicates that the protein recognizes this head group via an aromatic box, a typical choline-binding motif
- Although a potential substrate for SMPDL3B is sphingomyelin , we identify other possible substrates such as CDP-choline, ATP , and ADP
- Functional experiments employing structure-guided mutagenesis in macrophages highlight amino acid residues potentially involved in recognition of endogenous substrates
- Our study is an important step toward elucidating the specific function of this poorly characterized enzyme
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