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- PDB-8w9w: The cryo-EM structure of human sphingomyelin synthase-related pro... -

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Basic information

Entry
Database: PDB / ID: 8w9w
TitleThe cryo-EM structure of human sphingomyelin synthase-related protein in complex with ceramide/phosphoethanolamine
ComponentsSphingomyelin synthase-related protein 1
KeywordsMEMBRANE PROTEIN / synthase / sphingomyelin / CPE / lipid metabolism
Function / homology
Function and homology information


ceramide phosphoethanolamine biosynthetic process / ceramide phosphoethanolamine synthase activity / sphingomyelin synthase activity / ceramide cholinephosphotransferase activity / regulation of ceramide biosynthetic process / Transferases; Transferring phosphorus-containing groups; Transferases for other substituted phosphate groups / sphingomyelin biosynthetic process / sphingolipid biosynthetic process / Sphingolipid de novo biosynthesis / ceramide biosynthetic process ...ceramide phosphoethanolamine biosynthetic process / ceramide phosphoethanolamine synthase activity / sphingomyelin synthase activity / ceramide cholinephosphotransferase activity / regulation of ceramide biosynthetic process / Transferases; Transferring phosphorus-containing groups; Transferases for other substituted phosphate groups / sphingomyelin biosynthetic process / sphingolipid biosynthetic process / Sphingolipid de novo biosynthesis / ceramide biosynthetic process / endoplasmic reticulum membrane / endoplasmic reticulum / membrane / cytosol
Similarity search - Function
Sphingomyelin synthase-like / Sphingomyelin synthase-like domain / PAP2 superfamily C-terminal / SAM domain (Sterile alpha motif) / SAM domain profile. / Sterile alpha motif. / Sterile alpha motif domain / Sterile alpha motif/pointed domain superfamily
Similarity search - Domain/homology
PHOSPHORIC ACID MONO-(2-AMINO-ETHYL) ESTER / : / Sphingomyelin synthase-related protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.74 Å
AuthorsHu, K. / Zhang, Q. / Chen, Y. / Yao, D. / Zhou, L. / Cao, Y.
Funding support China, 2items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)82072468 China
National Natural Science Foundation of China (NSFC)82272519 China
CitationJournal: Nat Struct Mol Biol / Year: 2024
Title: Cryo-EM structure of human sphingomyelin synthase and its mechanistic implications for sphingomyelin synthesis.
Authors: Kexin Hu / Qing Zhang / Yang Chen / Jintong Yang / Ying Xia / Bing Rao / Shaobai Li / Yafeng Shen / Mi Cao / Hongliang Lu / An Qin / Xian-Cheng Jiang / Deqiang Yao / Jie Zhao / Lu Zhou / Yu Cao /
Abstract: Sphingomyelin (SM) has key roles in modulating mammalian membrane properties and serves as an important pool for bioactive molecules. SM biosynthesis is mediated by the sphingomyelin synthase (SMS) ...Sphingomyelin (SM) has key roles in modulating mammalian membrane properties and serves as an important pool for bioactive molecules. SM biosynthesis is mediated by the sphingomyelin synthase (SMS) family, comprising SMS1, SMS2 and SMS-related (SMSr) members. Although SMS1 and SMS2 exhibit SMS activity, SMSr possesses ceramide phosphoethanolamine synthase activity. Here we determined the cryo-electron microscopic structures of human SMSr in complexes with ceramide, diacylglycerol/phosphoethanolamine and ceramide/phosphoethanolamine (CPE). The structures revealed a hexameric arrangement with a reaction chamber located between the transmembrane helices. Within this structure, a catalytic pentad E-H/D-H-D was identified, situated at the interface between the lipophilic and hydrophilic segments of the reaction chamber. Additionally, the study unveiled the two-step synthesis process catalyzed by SMSr, involving PE-PLC (phosphatidylethanolamine-phospholipase C) hydrolysis and the subsequent transfer of the phosphoethanolamine moiety to ceramide. This research provides insights into the catalytic mechanism of SMSr and expands our understanding of sphingolipid metabolism.
History
DepositionSep 6, 2023Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Feb 28, 2024Provider: repository / Type: Initial release
Revision 1.1Mar 6, 2024Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title ..._citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Sphingomyelin synthase-related protein 1
B: Sphingomyelin synthase-related protein 1
C: Sphingomyelin synthase-related protein 1
D: Sphingomyelin synthase-related protein 1
E: Sphingomyelin synthase-related protein 1
F: Sphingomyelin synthase-related protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)189,71016
Polymers186,3396
Non-polymers3,37110
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Sphingomyelin synthase-related protein 1 / SMSr / Ceramide phosphoethanolamine synthase / CPE synthase / Sterile alpha motif domain-containing ...SMSr / Ceramide phosphoethanolamine synthase / CPE synthase / Sterile alpha motif domain-containing protein 8 / SAM domain-containing protein 8


Mass: 31056.529 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SAMD8 / Production host: Homo sapiens (human) / References: UniProt: Q96LT4, sphingomyelin synthase
#2: Chemical
ChemComp-UJO / ~{N}-[(~{Z},2~{S},3~{R})-1,3-bis(oxidanyl)heptadec-4-en-2-yl]dodecanamide


Mass: 467.768 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C29H57NO3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-OPE / PHOSPHORIC ACID MONO-(2-AMINO-ETHYL) ESTER / COLAMINE PHOSPHORIC ACID / Phosphorylethanolamine


Mass: 141.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H8NO4P / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: The cryo-EM structure of human sphingomyelin synthase-related protein in complex with ceramide/phosphoethanolamine
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2600 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.20.1_4487: / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.74 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 700891 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00813852
ELECTRON MICROSCOPYf_angle_d0.93418828
ELECTRON MICROSCOPYf_dihedral_angle_d12.6951874
ELECTRON MICROSCOPYf_chiral_restr0.0512052
ELECTRON MICROSCOPYf_plane_restr0.0092262

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