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- PDB-9b4f: Structure of human PSS1-P269S -

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Basic information

Entry
Database: PDB / ID: 9b4f
TitleStructure of human PSS1-P269S
ComponentsPhosphatidylserine synthase 1
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.27 Å
AuthorsLong, T. / Li, X.
Funding support United States, 1items
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, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 4, 2024Provider: repository / Type: Initial release
Revision 1.1Sep 11, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update
Revision 1.2Oct 16, 2024Group: Data collection / Database references / Structure summary
Category: citation / em_admin ...citation / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _em_admin.last_update / _pdbx_entry_details.has_protein_modification
Revision 1.3Oct 23, 2024Group: Data collection / Category: em_admin / Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Phosphatidylserine synthase 1
B: Phosphatidylserine synthase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)113,2354
Polymers113,1552
Non-polymers802
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Phosphatidylserine synthase 1 / PSS-1 / PtdSer synthase 1 / Serine-exchange enzyme I


Mass: 56577.312 Da / Num. of mol.: 2 / Mutation: P269S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PTDSS1, KIAA0024, PSSA / Production host: Homo sapiens (human)
References: UniProt: P48651, L-serine-phosphatidylethanolamine phosphatidyltransferase
#2: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ca
Has ligand of interestN
Has protein modificationY

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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: Human PSS1-P269S / 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: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.17_3644: / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.27 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 155373 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0035814
ELECTRON MICROSCOPYf_angle_d0.5617930
ELECTRON MICROSCOPYf_dihedral_angle_d13.3951942
ELECTRON MICROSCOPYf_chiral_restr0.043868
ELECTRON MICROSCOPYf_plane_restr0.004946

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