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- EMDB-44179: Structure of human PSS1-P269S -

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Basic information

Entry
Database: EMDB / ID: EMD-44179
TitleStructure of human PSS1-P269S
Map data
Sample
  • Complex: Human PSS1-P269S
    • Protein or peptide: Phosphatidylserine synthase 1
  • Ligand: CALCIUM ION
KeywordsMEMBRANE PROTEIN
Function / homology
Function and homology information


L-serine-phosphatidylethanolamine phosphatidyltransferase / L-serine-phosphatidylethanolamine phosphatidyltransferase activity / L-serine-phosphatidylcholine phosphatidyltransferase activity / Synthesis of PS / phosphatidylserine biosynthetic process / transferase activity / endoplasmic reticulum membrane / membrane
Similarity search - Function
Phosphatidyl serine synthase / Phosphatidyl serine synthase
Similarity search - Domain/homology
Phosphatidylserine synthase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.27 Å
AuthorsLong T / Li X
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM135343 United States
CitationJournal: Cell / Year: 2024
Title: Molecular insights into human phosphatidylserine synthase 1 reveal its inhibition promotes LDL uptake.
Authors: Tao Long / Dongyu Li / Goncalo Vale / Yaoyukun Jiang / Philip Schmiege / Zhongyue J Yang / Jeffrey G McDonald / Xiaochun Li /
Abstract: In mammalian cells, two phosphatidylserine (PS) synthases drive PS synthesis. Gain-of-function mutations in the Ptdss1 gene lead to heightened PS production, causing Lenz-Majewski syndrome (LMS). ...In mammalian cells, two phosphatidylserine (PS) synthases drive PS synthesis. Gain-of-function mutations in the Ptdss1 gene lead to heightened PS production, causing Lenz-Majewski syndrome (LMS). Recently, pharmacological inhibition of PSS1 has been shown to suppress tumorigenesis. Here, we report the cryo-EM structures of wild-type human PSS1 (PSS1), the LMS-causing Pro269Ser mutant (PSS1), and PSS1 in complex with its inhibitor DS55980254. PSS1 contains 10 transmembrane helices (TMs), with TMs 4-8 forming a catalytic core in the luminal leaflet. These structures revealed a working mechanism of PSS1 akin to the postulated mechanisms of the membrane-bound O-acyltransferase family. Additionally, we showed that both PS and DS55980254 can allosterically inhibit PSS1 and that inhibition by DS55980254 activates the SREBP pathways, thus enhancing the expression of LDL receptors and increasing cellular LDL uptake. This work uncovers a mechanism of mammalian PS synthesis and suggests that selective PSS1 inhibitors have the potential to lower blood cholesterol levels.
History
DepositionMar 20, 2024-
Header (metadata) releaseSep 4, 2024-
Map releaseSep 4, 2024-
UpdateOct 23, 2024-
Current statusOct 23, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_44179.png

Downloads & links

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Map

FileDownload / File: emd_44179.map.gz / Format: CCP4 / Size: 149.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.74 Å/pix.
x 340 pix.
= 250.92 Å		0.74 Å/pix.
x 340 pix.
= 250.92 Å		0.74 Å/pix.
x 340 pix.
= 250.92 Å

Surface

Projections

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.738 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.15
Minimum - Maximum-0.82685715 - 1.2340577
Average (Standard dev.)0.0010242659 (±0.022755876)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions340340340
Spacing340340340
CellA=B=C: 250.92 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_44179_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_44179_half_map_2.map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : Human PSS1-P269S

EntireName: Human PSS1-P269S
Components
  • Complex: Human PSS1-P269S
    • Protein or peptide: Phosphatidylserine synthase 1
  • Ligand: CALCIUM ION

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Supramolecule #1: Human PSS1-P269S

SupramoleculeName: Human PSS1-P269S / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Phosphatidylserine synthase 1

MacromoleculeName: Phosphatidylserine synthase 1 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
EC number: L-serine-phosphatidylethanolamine phosphatidyltransferase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 56.577312 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MASCVGSRTL SKDDVNYKMH FRMINEQQVE DITIDFFYRP HTITLLSFTI VSLMYFAFTR DDSVPEDNIW RGILSVIFFF LIISVLAFP NGPFTRPHPA LWRMVFGLSV LYFLFLVFLL FLNFEQVKSL MYWLDPNLRY ATREADVMEY AVNCHVITWE R IISHFDIF ...String:
MASCVGSRTL SKDDVNYKMH FRMINEQQVE DITIDFFYRP HTITLLSFTI VSLMYFAFTR DDSVPEDNIW RGILSVIFFF LIISVLAFP NGPFTRPHPA LWRMVFGLSV LYFLFLVFLL FLNFEQVKSL MYWLDPNLRY ATREADVMEY AVNCHVITWE R IISHFDIF AFGHFWGWAM KALLIRSYGL CWTISITWEL TELFFMHLLP NFAECWWDQV ILDILLCNGG GIWLGMVVCR FL EMRTYHW ASFKDIHTTT GKIKRAVLQF TSASWTYVRW FDPKSSFQRV AGVYLFMIIW QLTELNTFFL KHIFVFQASH PLS WGRILF IGGITAPTVR QYYAYLTDTQ CKRVGTQCWV FGVIGFLEAI VCIKFGQDLF SKTQILYVVL WLLCVAFTTF LCLY GMIWY AEHYGHREKT YSECEDGTYS PEISWHHRKG TKGSEDSPPK HAGNNESHSS RRRNRHSKSK VTNGVGKKDY KDDDD K

UniProtKB: Phosphatidylserine synthase 1

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Macromolecule #2: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 2 / Number of copies: 2 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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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: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.27 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 155373
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE

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