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John Tesmer Research Group

Molecular Basis of Phospholipase Activation

Since 2010, the lab has been investigating the process of interfacial activation in several families of mammalian phospholipases. These enzymes are potent esterases whose activity must be tightly regulated to prevent lipid hydrolysis at the wrong membranes or when appropriate extracellular signals are absent. The LPLA2/LCAT family of phospholipases transfers the sn2 acyl chain from lipids such as lecithin to acceptor lipids such as ceramide or cholesterol. These closely related enzymes are important for lung surfactant catabolism and for reverse cholesterol transport to the liver, respectively. They are both important targets for biotherapeutic development. The Tesmer lab has determined crystal structures for both LPLA2 and LCAT (1,2) and is working towards developing small molecular activators (3) and variants with improved activity that could be used to treat acute coronary syndrome and/or fatal genetic diseases that inhibit LCAT activity, such as familial LCAT deficiency. Structural characterization of LCAT in complex with HDL by cryo-EM single particle reconstruction (4) is another important goal.
Project 4
Publications

  1. Glukhova A, Hinkovska-Galcheva V, Kelly R, Abe A, Shayman JA, Tesmer JJ. Structure and function of lysosomal phospholipase A2 and lecithin:cholesterol acyltransferase. Nat Commun. 2015 6:6250. PMC4397983

  2. Hoadley-Manthei K, Ahn J, Glukhova A, Yuan W, Larkin C, Manett TD, Chang L, Shayman JA, Axley MJ, Schwendeman A, Shayman JA, Tesmer JJG: A retractable lid in lecithin:cholesterol acyltransferase provides a structural mechanism for activation by apolipoprotein A-I. J. Biol. Chem. 2017 292:20313-20327. PMC5724016

  3. Manthei KA, Yang S-M, Baljinnyam B, Glukhova A, Chang L, Yuan W, Freeman LA, Shen M, Maloney DJ, Schwendeman A, Remaley AT, Jadhav A, and Tesmer JJG: Molecular basis for activation of lecithin:cholesterol acyltransferase (LCAT) by a high affinity chemical probe. Elife, 2018 7: pii: e41604. doi: 10.7554/eLife.41604. PMC6277198

  4. Manthei KA, Patra D, Wilson CJ, Fawaz MV, Piersimoni L, Shenkar J, Yuan W, Andrews PC, Engen JR, Schwendeman A, Ohi MD, Tesmer JJG. Structure of lecithin:cholesterol acyltransferase bound to high density lipoprotein particles. Commun. Biol. 2020, 3:28. doi: 10.1038/s42003-019-0749-z. PMC6962161