21NW

Cryo-EM structure of human Lipid Phosphate Phosphatase 2

Summary for 21NW

• Entry DOI: 10.2210/pdb21nw/pdb
• EMDB information: 67854
• Descriptor: Phospholipid phosphatase 2, 1-PALMITOYL-2-LINOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE, 2-acetamido-2-deoxy-beta-D-glucopyranose (3 entities in total)
• Functional Keywords: phosphatidylcholine, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 134351.96

Authors

Wang, W.Y.,Han, L. (deposition date: 2025-12-21, release date: 2026-05-06, Last modification date: 2026-06-17)

Primary citation

Wang, W.,Xu, Y.,Guo, P.,Han, H.,Han, L.
Cryo-EM structure of human lipid phosphate phosphatase 2.
Structure, 34:955-, 2026

PubMed Abstract: Lipid phosphate phosphatases (LPPs) dephosphorylate lipid phosphates to regulate signaling and metabolism. Among the three mammalian isoforms, LPP1, LPP2, and LPP3, LPP2 has been strongly associated with cancer, making it a potential therapeutic target. However, the molecular mechanisms underlying its structural organization, substrate recognition, and catalysis remain elusive. Here, we report the cryo-EM structure of human LPP2 (hLPP2). hLPP2 assembles as a homo-tetramer, with phosphatidylcholine bound in the substrate pocket. The tetrameric arrangement provides a structural basis for LPP oligomerization. The wide, open-ended substrate pocket explains the enzyme's broad substrate specificity. Structural comparison with PAP2 family members, including hG6PC1 and ecPgpB, suggests a conserved catalytic mechanism and highlights the regulatory role of residue E159 in stabilizing the catalytic center and phosphate release. Collectively, these findings advance our understanding of the structural basis and enzymatic mechanism of LPPs and may provide insights for the development of novel cancer therapies.

PubMed: 42068977
DOI: 10.1016/j.str.2026.04.003

Experimental method

ELECTRON MICROSCOPY (2.9 Å)