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 () and Maojun Yang ()
Additional contact information
Jingbo Yi: Tsinghua University
Boya Qi: Tsinghua University
Jian Yin: Tsinghua University
Ruochong Li: Tsinghua University
Xudong Chen: Tsinghua University
Junhan Hu: Tsinghua University
Guohui Li: Chinese Academy of Sciences
Sensen Zhang: Tsinghua University
Yuebin Zhang: Chinese Academy of Sciences
Maojun Yang: Tsinghua University

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: 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.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-023-43580-w Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43580-w

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-43580-w

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().