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TitleMolecular insights into human phosphatidylserine synthase 1 reveal its inhibition promotes LDL uptake.
Journal, issue, pagesCell, Vol. 187, Issue 20, Page 5665-5678.e18, Year 2024
Publish dateOct 3, 2024
AuthorsTao Long / Dongyu Li / Goncalo Vale / Yaoyukun Jiang / Philip Schmiege / Zhongyue J Yang / Jeffrey G McDonald / Xiaochun Li /
PubMed AbstractIn 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.
External linksCell / PubMed:39208797 / PubMed Central
MethodsEM (single particle)
Resolution2.7 - 3.27 Å
Structure data

44178

9b4e

EMDB-44178, PDB-9b4e:
Structure of wild type human PSS1
Method: EM (single particle) / Resolution: 2.7 Å

44179

9b4f

EMDB-44179, PDB-9b4f:
Structure of human PSS1-P269S
Method: EM (single particle) / Resolution: 3.27 Å

44180

9b4g

EMDB-44180, PDB-9b4g:
Structure of inhibitor-bound human PSS1
Method: EM (single particle) / Resolution: 2.87 Å

Chemicals

ChemComp-P5S:
O-[(R)-{[(2R)-2,3-bis(octadecanoyloxy)propyl]oxy}(hydroxy)phosphoryl]-L-serine

ChemComp-LBN:
1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine / phospholipid*YM

PDB-1ais:
TATA-BINDING PROTEIN/TRANSCRIPTION FACTOR (II)B/TATA-BOX COMPLEX FROM PYROCOCCUS WOESEI

ChemComp-6OU:
[(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl] (~{Z})-octadec-9-enoate / phospholipid*YM

ChemComp-CA:
Unknown entry

ChemComp-HOH:
WATER

PDB-1ait:
Unknown entry

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN

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