7U9D

Crystal Structure of Human Phosphatidylcholine Transfer Protein in Complex with PC(16:0/20:4)

Summary for 7U9D

• Entry DOI: 10.2210/pdb7u9d/pdb
• Descriptor: Phosphatidylcholine transfer protein, [(2~{R})-1-hexadecanoyloxy-3-[oxidanyl-[2-(trimethyl-$l^{4}-azanyl)ethoxy]phosphoryl]oxy-propan-2-yl] (5~{Z},8~{Z},11~{Z},14~{Z})-icosa-5,8,11,14-tetraenoate, GLYCEROL, ... (4 entities in total)
• Functional Keywords: phosphatidylcholine transfer protein, pc(16:0/20:4), complex, ligand, lipid binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 25746.49

Authors

Druzak, S.A. (deposition date: 2022-03-10, release date: 2023-04-12, Last modification date: 2024-11-13)

Primary citation

Druzak, S.A.,Tardelli, M.,Mays, S.G.,El Bejjani, M.,Mo, X.,Maner-Smith, K.M.,Bowen, T.,Cato, M.L.,Tillman, M.C.,Sugiyama, A.,Xie, Y.,Fu, H.,Cohen, D.E.,Ortlund, E.A.
Ligand dependent interaction between PC-TP and PPAR delta mitigates diet-induced hepatic steatosis in male mice.
Nat Commun, 14:2748-2748, 2023

PubMed Abstract: Phosphatidylcholine transfer protein (PC-TP; synonym StarD2) is a soluble lipid-binding protein that transports phosphatidylcholine (PC) between cellular membranes. To better understand the protective metabolic effects associated with hepatic PC-TP, we generated a hepatocyte-specific PC-TP knockdown (L-Pctp) in male mice, which gains less weight and accumulates less liver fat compared to wild-type mice when challenged with a high-fat diet. Hepatic deletion of PC-TP also reduced adipose tissue mass and decreases levels of triglycerides and phospholipids in skeletal muscle, liver and plasma. Gene expression analysis suggest that the observed metabolic changes are related to transcriptional activity of peroxisome proliferative activating receptor (PPAR) family members. An in-cell protein complementation screen between lipid transfer proteins and PPARs uncovered a direct interaction between PC-TP and PPARδ that was not observed for other PPARs. We confirmed the PC-TP- PPARδ interaction in Huh7 hepatocytes, where it was found to repress PPARδ-mediated transactivation. Mutations of PC-TP residues implicated in PC binding and transfer reduce the PC-TP-PPARδ interaction and relieve PC-TP-mediated PPARδ repression. Reduction of exogenously supplied methionine and choline reduces the interaction while serum starvation enhances the interaction in cultured hepatocytes. Together our data points to a ligand sensitive PC-TP- PPARδ interaction that suppresses PPAR activity.

PubMed: 37173315
DOI: 10.1038/s41467-023-38010-w

Experimental method

X-RAY DIFFRACTION (2.18 Å)