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Structure and function of lysosomal phospholipase A2 and lecithin:cholesterol acyltransferase.

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Glukhova A, Hinkovska-Galcheva V, Kelly R, Abe A, Shayman JA, Tesmer JJ
OpenAccess logo Nat Commun 6 6250 (2015)
Related entries: 4x90, 4x92, 4x93, 4x94, 4x95, 4x96, 4x97

Cited: 43 times
EuropePMC logo PMID: 25727495

Abstract

Lysosomal phospholipase A2 (LPLA2) and lecithin:cholesterol acyltransferase (LCAT) belong to a structurally uncharacterized family of key lipid-metabolizing enzymes responsible for lung surfactant catabolism and for reverse cholesterol transport, respectively. Whereas LPLA2 is predicted to underlie the development of drug-induced phospholipidosis, somatic mutations in LCAT cause fish eye disease and familial LCAT deficiency. Here we describe several high-resolution crystal structures of human LPLA2 and a low-resolution structure of LCAT that confirms its close structural relationship to LPLA2. Insertions in the α/β hydrolase core of LPLA2 form domains that are responsible for membrane interaction and binding the acyl chains and head groups of phospholipid substrates. The LCAT structure suggests the molecular basis underlying human disease for most of the known LCAT missense mutations, and paves the way for rational development of new therapeutics to treat LCAT deficiency, atherosclerosis and acute coronary syndrome.

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  1. Zinc Finger Readers of Methylated DNA. Hudson NO, Buck-Koehntop BA. Molecules 23 E2555 (2018)

Articles - 4x91 mentioned but not cited (6)

  1. Structure and function of lysosomal phospholipase A2 and lecithin:cholesterol acyltransferase. Glukhova A, Hinkovska-Galcheva V, Kelly R, Abe A, Shayman JA, Tesmer JJ. Nat Commun 6 6250 (2015)
  2. A Lipolytic Lecithin:Cholesterol Acyltransferase Secreted by Toxoplasma Facilitates Parasite Replication and Egress. Pszenny V, Ehrenman K, Romano JD, Kennard A, Schultz A, Roos DS, Grigg ME, Carruthers VB, Coppens I. J Biol Chem 291 3725-3746 (2016)
  3. A retractable lid in lecithin:cholesterol acyltransferase provides a structural mechanism for activation by apolipoprotein A-I. Manthei KA, Ahn J, Glukhova A, Yuan W, Larkin C, Manett TD, Chang L, Shayman JA, Axley MJ, Schwendeman A, Tesmer JJG. J Biol Chem 292 20313-20327 (2017)
  4. Molecular basis for activation of lecithin:cholesterol acyltransferase by a compound that increases HDL cholesterol. Manthei KA, Yang SM, Baljinnyam B, Chang L, Glukhova A, Yuan W, Freeman LA, Maloney DJ, Schwendeman A, Remaley AT, Jadhav A, Tesmer JJ. Elife 7 e41604 (2018)
  5. Structural Basis of Lysosomal Phospholipase A2 Inhibition by Zn2. Bouley RA, Hinkovska-Galcheva V, Shayman JA, Tesmer JJG. Biochemistry 58 1709-1717 (2019)
  6. The Phospholipid:Diacylglycerol Acyltransferase-Mediated Acyl-Coenzyme A-Independent Pathway Efficiently Diverts Fatty Acid Flux from Phospholipid into Triacylglycerol in Escherichia coli. Wang L, Jiang S, Chen WC, Zhou XR, Huang TX, Huang FH, Wan X. Appl Environ Microbiol 86 e00999-20 (2020)


Reviews citing this publication (4)

  1. Properties and Biotechnological Applications of Acyl-CoA:diacylglycerol Acyltransferase and Phospholipid:diacylglycerol Acyltransferase from Terrestrial Plants and Microalgae. Xu Y, Caldo KMP, Pal-Nath D, Ozga J, Lemieux MJ, Weselake RJ, Chen G. Lipids 53 663-688 (2018)
  2. Lysosomal phospholipase A2. Shayman JA, Tesmer JJG. Biochim Biophys Acta Mol Cell Biol Lipids 1864 932-940 (2019)
  3. Inhibition of lysosomal phospholipase A2 predicts drug-induced phospholipidosis. Hinkovska-Galcheva V, Treadwell T, Shillingford JM, Lee A, Abe A, Tesmer JJG, Shayman JA. J Lipid Res 62 100089 (2021)
  4. Relationships of human α/β hydrolase fold proteins and other organophosphate-interacting proteins. Lenfant N, Bourne Y, Marchot P, Chatonnet A. Chem Biol Interact 259 343-351 (2016)

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  6. Lecithin:Cholesterol Acyltransferase Activation by Sulfhydryl-Reactive Small Molecules: Role of Cysteine-31. Freeman LA, Demosky SJ, Konaklieva M, Kuskovsky R, Aponte A, Ossoli AF, Gordon SM, Koby RF, Manthei KA, Shen M, Vaisman BL, Shamburek RD, Jadhav A, Calabresi L, Gucek M, Tesmer JJG, Levine RL, Remaley AT. J Pharmacol Exp Ther 362 306-318 (2017)
  7. Structural analysis of lecithin:cholesterol acyltransferase bound to high density lipoprotein particles. Manthei KA, Patra D, Wilson CJ, Fawaz MV, Piersimoni L, Shenkar JC, Yuan W, Andrews PC, Engen JR, Schwendeman A, Ohi MD, Tesmer JJG. Commun Biol 3 28 (2020)
  8. Congress Lecithin:cholesterol acyltransferase: symposium on 50 years of biomedical research from its discovery to latest findings. Norum KR, Remaley AT, Miettinen HE, Strøm EH, Balbo BEP, Sampaio CATL, Wiig I, Kuivenhoven JA, Calabresi L, Tesmer JJ, Zhou M, Ng DS, Skeie B, Karathanasis SK, Manthei KA, Retterstøl K. J Lipid Res 61 1142-1149 (2020)
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