Structural Basis for Nucleotide Hydrolysis by the Acid Sphingomyelinase-like Phosphodiesterase SMPDL3A.

The Journal of Biological Chemistry
Alexei GorelikBhushan Nagar

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...Continue Reading

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Citations

Jun 25, 2016·American Journal of Medical Genetics. Part a·Prajnya RanganathAshwin Dalal
Jul 21, 2016·Nature Communications·Alexei GorelikBhushan Nagar
Jan 19, 2018·Matrix Biology : Journal of the International Society for Matrix Biology·Andrea Huwiler, Josef Pfeilschifter
Feb 8, 2018·Journal of Proteome Research·Cristina Pérez-PatiñoJordi Roca

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