Nature Communications (Nov 2023)

Molecular basis for the catalytic mechanism of human neutral sphingomyelinases 1 (hSMPD2)

  • Jingbo Yi,
  • Boya Qi,
  • Jian Yin,
  • Ruochong Li,
  • Xudong Chen,
  • Junhan Hu,
  • Guohui Li,
  • Sensen Zhang,
  • Yuebin Zhang,
  • Maojun Yang

DOI
https://doi.org/10.1038/s41467-023-43580-w
Journal volume & issue
Vol. 14, no. 1
pp. 1 – 13

Abstract

Read online

Abstract Enzymatic breakdown of sphingomyelin by sphingomyelinase (SMase) is the main source of the membrane lipids, ceramides, which are involved in many cellular physiological processes. However, the full-length structure of human neutral SMase has not been resolved; therefore, its catalytic mechanism remains unknown. Here, we resolve the structure of human full-length neutral SMase, sphingomyelinase 1 (SMPD2), which reveals that C-terminal transmembrane helices contribute to dimeric architecture of hSMPD2 and that D111 − K116 loop domain is essential for substrate hydrolysis. Coupled with molecular docking, we clarify the binding pose of sphingomyelin, and site-directed mutagenesis further confirms key residues responsible for sphingomyelin binding. Hybrid quantum mechanics/molecular mechanics (QM/MM) molecular dynamic (MD) simulations are utilized to elaborate the catalysis of hSMPD2 with the reported in vitro substrates, sphingomyelin and lyso-platelet activating fator (lyso-PAF). Our study provides mechanistic details that enhance our knowledge of lipid metabolism and may lead to an improved understanding of ceramide in disease and in cancer treatment.