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- EMDB-30080: Cryo-EM structure of the monomeric SPT-ORMDL3 complex -

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Basic information

Entry
Database: EMDB / ID: EMD-30080
TitleCryo-EM structure of the monomeric SPT-ORMDL3 complex
Map data
Sample
  • Complex: membrane protein 2Biological membrane
    • Protein or peptide: Serine palmitoyltransferase 1Serine C-palmitoyltransferase
    • Protein or peptide: Serine palmitoyltransferase 2Serine C-palmitoyltransferase
    • Protein or peptide: ORM1-like protein 3
    • Protein or peptide: Serine palmitoyltransferase small subunit ASerine C-palmitoyltransferase
  • Ligand: PYRIDOXAL-5'-PHOSPHATEPyridoxal phosphate
Function / homology
Function and homology information


negative regulation of ceramide biosynthetic process / sphinganine biosynthetic process / regulation of fat cell apoptotic process / serine C-palmitoyltransferase complex / sphingomyelin biosynthetic process / SPOTS complex / intracellular sphingolipid homeostasis / serine C-palmitoyltransferase activity / serine C-palmitoyltransferase / sphingolipid biosynthetic process ...negative regulation of ceramide biosynthetic process / sphinganine biosynthetic process / regulation of fat cell apoptotic process / serine C-palmitoyltransferase complex / sphingomyelin biosynthetic process / SPOTS complex / intracellular sphingolipid homeostasis / serine C-palmitoyltransferase activity / serine C-palmitoyltransferase / sphingolipid biosynthetic process / Sphingolipid de novo biosynthesis / sphingosine biosynthetic process / regulation of smooth muscle contraction / ceramide biosynthetic process / ceramide metabolic process / sphingolipid metabolic process / negative regulation of B cell apoptotic process / motor behavior / positive regulation of lipophagy / adipose tissue development / specific granule membrane / positive regulation of autophagy / myelination / secretory granule membrane / protein localization / positive regulation of protein localization to nucleus / pyridoxal phosphate binding / Neutrophil degranulation / endoplasmic reticulum membrane / endoplasmic reticulum / plasma membrane
Similarity search - Function
Small subunit of serine palmitoyltransferase-like / Small subunit of serine palmitoyltransferase-like / ORMDL family / ORMDL family / Aminotransferase, class-II, pyridoxal-phosphate binding site / Aminotransferases class-II pyridoxal-phosphate attachment site. / Aminotransferase, class I/classII / Aminotransferase class I and II / Pyridoxal phosphate-dependent transferase, small domain / Pyridoxal phosphate-dependent transferase, major domain / Pyridoxal phosphate-dependent transferase
Similarity search - Domain/homology
Serine palmitoyltransferase 1 / Serine palmitoyltransferase 2 / ORM1-like protein 3 / Serine palmitoyltransferase small subunit A
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsLi SS / 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.
History
DepositionMar 8, 2020-
Header (metadata) releaseFeb 10, 2021-
Map releaseFeb 10, 2021-
UpdateMar 24, 2021-
Current statusMar 24, 2021Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.032
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.032
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6m4o
  • Surface level: 0.032
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_30080.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.114 Å
Density
Contour LevelBy AUTHOR: 0.032 / Movie #1: 0.032
Minimum - Maximum-0.11677427 - 0.15322934
Average (Standard dev.)-2.1373044e-06 (±0.0035765236)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 356.47998 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.1141.1141.114
M x/y/z320320320
origin x/y/z0.0000.0000.000
length x/y/z356.480356.480356.480
α/β/γ90.00090.00090.000
start NX/NY/NZ1219875
NX/NY/NZ141223232
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS320320320
D min/max/mean-0.1170.153-0.000

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Supplemental data

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Sample components

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Entire : membrane protein 2

EntireName: membrane protein 2Biological membrane
Components
  • Complex: membrane protein 2Biological membrane
    • Protein or peptide: Serine palmitoyltransferase 1Serine C-palmitoyltransferase
    • Protein or peptide: Serine palmitoyltransferase 2Serine C-palmitoyltransferase
    • Protein or peptide: ORM1-like protein 3
    • Protein or peptide: Serine palmitoyltransferase small subunit ASerine C-palmitoyltransferase
  • Ligand: PYRIDOXAL-5'-PHOSPHATEPyridoxal phosphate

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Supramolecule #1: membrane protein 2

SupramoleculeName: membrane protein 2 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)

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Macromolecule #1: Serine palmitoyltransferase 1

MacromoleculeName: Serine palmitoyltransferase 1 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: serine C-palmitoyltransferase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 52.80677 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MATATEQWVL VEMVQALYEA PAYHLILEGI LILWIIRLLF SKTYKLQERS DLTVKEKEEL IEEWQPEPLV PPVPKDHPAL NYNIVSGPP SHKTVVNGKE CINFASFNFL GLLDNPRVKA AALASLKKYG VGTCGPRGFY GTFDVHLDLE DRLAKFMKTE E AIIYSYGF ...String:
MATATEQWVL VEMVQALYEA PAYHLILEGI LILWIIRLLF SKTYKLQERS DLTVKEKEEL IEEWQPEPLV PPVPKDHPAL NYNIVSGPP SHKTVVNGKE CINFASFNFL GLLDNPRVKA AALASLKKYG VGTCGPRGFY GTFDVHLDLE DRLAKFMKTE E AIIYSYGF ATIASAIPAY SKRGDIVFVD RAACFAIQKG LQASRSDIKL FKHNDMADLE RLLKEQEIED QKNPRKARVT RR FIVVEGL YMNTGTICPL PELVKLKYKY KARIFLEESL SFGVLGEHGR GVTEHYGINI DDIDLISANM ENALASIGGF CCG RSFVID HQRLSGQGYC FSASLPPLLA AAAIEALNIM EENPGIFAVL KEKCGQIHKA LQGISGLKVV GESLSPAFHL QLEE STGSR EQDVRLLQEI VDQCMNRSIA LTQARYLEKE EKCLPPPSIR VVVTVEQTEE ELERAASTIK EVAQAVLL

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Macromolecule #2: Serine palmitoyltransferase 2

MacromoleculeName: Serine palmitoyltransferase 2 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: serine C-palmitoyltransferase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 63.00416 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MRPEPGGCCC RRTVRANGCV ANGEVRNGYV RSSAAAAAAA AAGQIHHVTQ NGGLYKRPFN EAFEETPMLV AVLTYVGYGV LTLFGYLRD FLRYWRIEKC HHATEREEQK DFVSLYQDFE NFYTRNLYMR IRDNWNRPIC SVPGARVDIM ERQSHDYNWS F KYTGNIIK ...String:
MRPEPGGCCC RRTVRANGCV ANGEVRNGYV RSSAAAAAAA AAGQIHHVTQ NGGLYKRPFN EAFEETPMLV AVLTYVGYGV LTLFGYLRD FLRYWRIEKC HHATEREEQK DFVSLYQDFE NFYTRNLYMR IRDNWNRPIC SVPGARVDIM ERQSHDYNWS F KYTGNIIK GVINMGSYNY LGFARNTGSC QEAAAKVLEE YGAGVCSTRQ EIGNLDKHEE LEELVARFLG VEAAMAYGMG FA TNSMNIP ALVGKGCLIL SDELNHASLV LGARLSGATI RIFKHNNMQS LEKLLKDAIV YGQPRTRRPW KKILILVEGI YSM EGSIVR LPEVIALKKK YKAYLYLDEA HSIGALGPTG RGVVEYFGLD PEDVDVMMGT FTKSFGASGG YIGGKKELID YLRT HSHSA VYATSLSPPV VEQIITSMKC IMGQDGTSLG KECVQQLAEN TRYFRRRLKE MGFIIYGNED SPVVPLMLYM PAKIG AFGR EMLKRNIGVV VVGFPATPII ESRARFCLSA AHTKEILDTA LKEIDEVGDL LQLKYSRHRL VPLLDRPFDE TTYEET ED

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Macromolecule #3: ORM1-like protein 3

MacromoleculeName: ORM1-like protein 3 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 17.512594 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
MNVGTAHSEV NPNTRVMNSR GIWLSYVLAI GLLHIVLLSI PFVSVPVVWT LTNLIHNMGM YIFLHTVKGT PFETPDQGKA RLLTHWEQM DYGVQFTASR KFLTITPIVL YFLTSFYTKY DQIHFVLNTV SLMSVLIPKL PQLHGVRIFG INKY

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Macromolecule #4: Serine palmitoyltransferase small subunit A

MacromoleculeName: Serine palmitoyltransferase small subunit A / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 10.742409 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
MADYKDDDDK SGPDEVDASG RMAGMALARA WKQMSWFYYQ YLLVTALYML EPWERTVFNS MLVSIVGMAL YTGYVFMPQH IMAILHYFE IVQ

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Macromolecule #5: PYRIDOXAL-5'-PHOSPHATE

MacromoleculeName: PYRIDOXAL-5'-PHOSPHATE / type: ligand / ID: 5 / Number of copies: 1 / Formula: PLP
Molecular weightTheoretical: 247.142 Da
Chemical component information

ChemComp-PLP:
PYRIDOXAL-5'-PHOSPHATE / Pyridoxal phosphate

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 59924

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