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TitleStructural basis of PLPP3-mediated lipid phosphate dephosphorylation and its role in melanoma.
Journal, issue, pagesNat Commun, Year 2026
Publish dateJul 20, 2026
AuthorsYingjie Wu / Di Xiao / Xingfan Li / Keyu Wang / Hongxu Zhang / Yuanyuan Zhao / Di Wu / Ruxi Qi / Mi Zhou / Han Han / Tao Long /
PubMed AbstractLipid phosphates serve as signaling molecules involved in diverse cellular processes such as cell proliferation, migration, angiogenesis, inflammation, immunity and cancer progression. Phospholipid ...Lipid phosphates serve as signaling molecules involved in diverse cellular processes such as cell proliferation, migration, angiogenesis, inflammation, immunity and cancer progression. Phospholipid phosphatases (PLPPs) modulate these signals by catalyzing the dephosphorylation of lipid phosphates. Here, we report the cryo-EM structure of PLPP3, revealing a tetrameric assembly. PLPP3 contains six transmembrane helices (TMs) and an extracellular domain that contains two extracellular loops. TMs 1-4 create a hydrophobic cleft that holds the tails of a phospholipid while the extracellular domain forms a positively charged pocket to accommodate the polar head group. Two conserved catalytic histidine residues in this pocket coordinate a putative zinc ion previously identified as a PLPP3 inhibitor. Structural mapping of somatic mutations with functional analysis reveals that PLPP3 acts as a tumor suppressor in melanoma. Together, our findings provide critical insights into the structure, substrate engagement, inhibitory mechanism, and cancer-related function of PLPP3.
External linksNat Commun / PubMed:42477009
MethodsEM (single particle)
Resolution2.79 - 2.9 Å
Structure data

80306

25qp

EMDB-80306, PDB-25qp:
Cryo-EM Structure of PLPP3
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-81156: Structure of PLPP3 prepared in the presence of EDTA
Method: EM (single particle) / Resolution: 2.79 Å

Chemicals

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

ChemComp-PX2:
1,2-DILAUROYL-SN-GLYCERO-3-PHOSPHATE

ChemComp-ZN:
Unknown entry

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / Phosphatase

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