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- PDB-6m4o: Cryo-EM structure of the monomeric SPT-ORMDL3 complex -

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Basic information

Entry
Database: PDB / ID: 6m4o
TitleCryo-EM structure of the monomeric SPT-ORMDL3 complex
Components
  • ORM1-like protein 3
  • Serine palmitoyltransferase 1Serine C-palmitoyltransferase
  • Serine palmitoyltransferase 2Serine C-palmitoyltransferase
  • Serine palmitoyltransferase small subunit ASerine C-palmitoyltransferase
KeywordsTRANSFERASE / membrane protein / lipid synthesis
Function / homology
Function and homology information


negative regulation of serine C-palmitoyltransferase activity / negative regulation of ceramide biosynthetic process / cellular sphingolipid homeostasis / sphinganine biosynthetic process / serine C-palmitoyltransferase complex / regulation of fat cell apoptotic process / sphingomyelin biosynthetic process / serine C-palmitoyltransferase / serine C-palmitoyltransferase activity / SPOTS complex ...negative regulation of serine C-palmitoyltransferase activity / negative regulation of ceramide biosynthetic process / cellular sphingolipid homeostasis / sphinganine biosynthetic process / serine C-palmitoyltransferase complex / regulation of fat cell apoptotic process / sphingomyelin biosynthetic process / serine C-palmitoyltransferase / serine C-palmitoyltransferase activity / SPOTS complex / regulation of smooth muscle contraction / sphingosine biosynthetic process / sphingolipid biosynthetic process / ceramide biosynthetic process / ceramide metabolic process / positive regulation of lipophagy / sphingolipid metabolic process / motor behavior / negative regulation of B cell apoptotic process / myelination / adipose tissue development / specific granule membrane / positive regulation of autophagy / secretory granule membrane / positive regulation of protein localization to nucleus / pyridoxal phosphate binding / protein localization / endoplasmic reticulum membrane / neutrophil degranulation / endoplasmic reticulum / integral component of membrane / plasma membrane
Small subunit of serine palmitoyltransferase-like / Pyridoxal phosphate-dependent transferase, small domain / Aminotransferase, class-II, pyridoxal-phosphate binding site / Aminotransferase, class I/classII / ORMDL family / Pyridoxal phosphate-dependent transferase, major domain / Pyridoxal phosphate-dependent transferase / Small subunit of serine palmitoyltransferase-like / ORM1-like protein 3 / ORMDL family / Aminotransferase class I and II
Serine palmitoyltransferase 1 / Serine palmitoyltransferase 2 / ORM1-like protein 3 / Serine palmitoyltransferase small subunit A
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsLi, S.S. / Xie, T. / Wang, L. / Gong, X.
CitationJournal: Nat Struct Mol Biol / Year: 2021
Title: Structural insights into the assembly and substrate selectivity of human SPT-ORMDL3 complex.
Authors: Sisi Li / Tian Xie / Peng Liu / Lei Wang / Xin Gong /
Abstract: Human serine palmitoyltransferase (SPT) complex catalyzes the initial and rate-limiting step in the de novo biosynthesis of all sphingolipids. ORMDLs regulate SPT function, with human ORMDL3 being ...Human serine palmitoyltransferase (SPT) complex catalyzes the initial and rate-limiting step in the de novo biosynthesis of all sphingolipids. ORMDLs regulate SPT function, with human ORMDL3 being related to asthma. Here we report three high-resolution cryo-EM structures: the human SPT complex, composed of SPTLC1, SPTLC2 and SPTssa; the SPT-ORMDL3 complex; and the SPT-ORMDL3 complex bound to two substrates, PLP-L-serine (PLS) and a non-reactive palmitoyl-CoA analogue. SPTLC1 and SPTLC2 form a dimer of heterodimers as the catalytic core. SPTssa participates in acyl-CoA coordination, thereby stimulating the SPT activity and regulating the substrate selectivity. ORMDL3 is located in the center of the complex, serving to stabilize the SPT assembly. Our structural and biochemical analyses provide a molecular basis for the assembly and substrate selectivity of the SPT and SPT-ORMDL3 complexes, and lay a foundation for mechanistic understanding of sphingolipid homeostasis and for related therapeutic drug development.
Validation Report
SummaryFull reportAbout validation report
History
DepositionMar 8, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 10, 2021Provider: repository / Type: Initial release
Revision 1.1Feb 24, 2021Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation_author.name
Revision 1.2Mar 24, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

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Assembly

Deposited unit
S: Serine palmitoyltransferase 1
T: Serine palmitoyltransferase 2
A: ORM1-like protein 3
E: Serine palmitoyltransferase small subunit A
B: Serine palmitoyltransferase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)197,1206
Polymers196,8735
Non-polymers2471
Water0
1


TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Serine palmitoyltransferase 1 / Serine C-palmitoyltransferase / Long chain base biosynthesis protein 1 / LCB 1 / Serine-palmitoyl-CoA transferase 1 / SPT1


Mass: 52806.770 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SPTLC1, LCB1 / Production host: Homo sapiens (human) / References: UniProt: O15269, serine C-palmitoyltransferase
#2: Protein Serine palmitoyltransferase 2 / Serine C-palmitoyltransferase / Long chain base biosynthesis protein 2 / LCB 2 / Long chain base biosynthesis protein 2a / LCB2a / ...Long chain base biosynthesis protein 2 / LCB 2 / Long chain base biosynthesis protein 2a / LCB2a / Serine-palmitoyl-CoA transferase 2 / SPT 2


Mass: 63004.160 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SPTLC2, KIAA0526, LCB2 / Production host: Homo sapiens (human) / References: UniProt: O15270, serine C-palmitoyltransferase
#3: Protein ORM1-like protein 3


Mass: 17512.594 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ORMDL3 / Production host: Homo sapiens (human) / References: UniProt: Q8N138
#4: Protein Serine palmitoyltransferase small subunit A / Serine C-palmitoyltransferase / Small subunit of serine palmitoyltransferase A / ssSPTa


Mass: 10742.409 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SPTSSA, C14orf147, SSSPTA / Production host: Homo sapiens (human) / References: UniProt: Q969W0
#5: Chemical ChemComp-PLP / PYRIDOXAL-5'-PHOSPHATE / VITAMIN B6 Phosphate / Pyridoxal phosphate


Mass: 247.142 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H10NO6P / 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: membrane protein 2Biological membrane / Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
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: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 59924 / Symmetry type: POINT

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