Spectroscopic Analyses of the Binding Kinetics of 15d-PGJ2 to the PPARgamma Ligand-binding Domain by Multi-wavelength Global Fitting

Overview

Journal Biochem J

Specialty Biochemistry

Date 2005 Oct 21

PMID 16236024

Citations 7

Authors

Takuma Shiraki

Takashi S Kodama

Sayaka Shiki

Tatsuo Nakagawa

Hisato Jingami

Affiliations

Soon will be listed here.

Abstract

PPARgamma (peroxisome proliferator-activated receptor gamma) is a nuclear receptor that is activated by natural lipid metabolites, including 15d-PGJ2 (15-deoxy-Delta(12,14)-prostaglandin J2). We previously reported that several oxidized lipid metabolites covalently bind to PPARgamma through a Michael-addition to activate transcription. To separate the ligand-entering (dock) and covalent-binding (lock) steps in PPARgamma activation, we investigated the binding kinetics of 15d-PGJ2 to the PPARgamma LBD (ligand-binding domain) by stopped-flow spectroscopy. We analysed the spectral changes of 15d-PGJ2 by multi-wavelength global fitting based on a two-step chemical reaction model, in which an intermediate state represents the 15d-PGJ2-PPARgamma complex without covalent binding. The extracted spectrum of the intermediate state in wild-type PPARgamma was quite similar to the observed spectrum of 15d-PGJ2 in the C285S mutant, which cannot be activated by 15d-PGJ2, indicating that the complex remains in the inactive, intermediate state in the mutant. Thus 'lock' rather than 'dock' is one of the critical steps in PPARgamma activation by 15d-PGJ2.

Citing Articles

Self-regulation of the inflammatory response by peroxisome proliferator-activated receptors.

Korbecki J, Bobinski R, Dutka M Inflamm Res. 2019; 68(6):443-458.

PMID: 30927048 PMC: 6517359. DOI: 10.1007/s00011-019-01231-1.

Prostaglandin metabolite induces inhibition of TRPA1 and channel-dependent nociception.

Weng Y, Batista-Schepman P, Barabas M, Harris E, Dinsmore T, Kossyreva E Mol Pain. 2012; 8:75.

PMID: 23013719 PMC: 3526547. DOI: 10.1186/1744-8069-8-75.

Systemic PPARγ deletion impairs circadian rhythms of behavior and metabolism.

Yang G, Jia Z, Aoyagi T, McClain D, Mortensen R, Yang T PLoS One. 2012; 7(8):e38117.

PMID: 22899986 PMC: 3416825. DOI: 10.1371/journal.pone.0038117.

Nitro-fatty acids and cyclopentenone prostaglandins share strategies to activate the Keap1-Nrf2 system: a study using green fluorescent protein transgenic zebrafish.

Tsujita T, Li L, Nakajima H, Iwamoto N, Nakajima-Takagi Y, Ohashi K Genes Cells. 2010; 16(1):46-57.

PMID: 21143560 PMC: 4124525. DOI: 10.1111/j.1365-2443.2010.01466.x.

Covalent peroxisome proliferator-activated receptor gamma adduction by nitro-fatty acids: selective ligand activity and anti-diabetic signaling actions.

Schopfer F, Cole M, Groeger A, Chen C, Khoo N, Woodcock S J Biol Chem. 2010; 285(16):12321-33.

PMID: 20097754 PMC: 2852971. DOI: 10.1074/jbc.M109.091512.

References

Glass C, Rosenfeld M . The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev. 2000; 14(2):121-41. View

Shiraki T, Kamiya N, Shiki S, Kodama T, Kakizuka A, Jingami H . Alpha,beta-unsaturated ketone is a core moiety of natural ligands for covalent binding to peroxisome proliferator-activated receptor gamma. J Biol Chem. 2005; 280(14):14145-53. DOI: 10.1074/jbc.M500901200. View

Gampe Jr R, Montana V, Lambert M, Miller A, Bledsoe R, Milburn M . Asymmetry in the PPARgamma/RXRalpha crystal structure reveals the molecular basis of heterodimerization among nuclear receptors. Mol Cell. 2000; 5(3):545-55. DOI: 10.1016/s1097-2765(00)80448-7. View

Cronet P, Petersen J, Folmer R, Blomberg N, Sjoblom K, Karlsson U . Structure of the PPARalpha and -gamma ligand binding domain in complex with AZ 242; ligand selectivity and agonist activation in the PPAR family. Structure. 2001; 9(8):699-706. DOI: 10.1016/s0969-2126(01)00634-7. View

Xu H, Lambert M, Montana V, Plunket K, Moore L, Collins J . Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors. Proc Natl Acad Sci U S A. 2001; 98(24):13919-24. PMC: 61142. DOI: 10.1073/pnas.241410198. View

Willson T, Lambert M, Kliewer S . Peroxisome proliferator-activated receptor gamma and metabolic disease. Annu Rev Biochem. 2001; 70:341-67. DOI: 10.1146/annurev.biochem.70.1.341. View

Xu H, Stanley T, Montana V, Lambert M, Shearer B, Cobb J . Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPARalpha. Nature. 2002; 415(6873):813-7. DOI: 10.1038/415813a. View

Leesnitzer L, Parks D, Bledsoe R, Cobb J, Collins J, Consler T . Functional consequences of cysteine modification in the ligand binding sites of peroxisome proliferator activated receptors by GW9662. Biochemistry. 2002; 41(21):6640-50. DOI: 10.1021/bi0159581. View

Lee G, Elwood F, McNally J, Weiszmann J, Lindstrom M, Amaral K . T0070907, a selective ligand for peroxisome proliferator-activated receptor gamma, functions as an antagonist of biochemical and cellular activities. J Biol Chem. 2002; 277(22):19649-57. DOI: 10.1074/jbc.M200743200. View

10.

McIntyre T, Pontsler A, Silva A, St Hilaire A, Xu Y, Hinshaw J . Identification of an intracellular receptor for lysophosphatidic acid (LPA): LPA is a transcellular PPARgamma agonist. Proc Natl Acad Sci U S A. 2002; 100(1):131-6. PMC: 140905. DOI: 10.1073/pnas.0135855100. View

11.

Kallenberger B, Love J, Chatterjee V, Schwabe J . A dynamic mechanism of nuclear receptor activation and its perturbation in a human disease. Nat Struct Biol. 2003; 10(2):136-40. DOI: 10.1038/nsb892. View

12.

Li Y, Lambert M, Xu H . Activation of nuclear receptors: a perspective from structural genomics. Structure. 2003; 11(7):741-6. DOI: 10.1016/s0969-2126(03)00133-3. View

13.

Tamrazi A, Carlson K, Katzenellenbogen J . Molecular sensors of estrogen receptor conformations and dynamics. Mol Endocrinol. 2003; 17(12):2593-602. DOI: 10.1210/me.2003-0239. View

14.

Evans R, Barish G, Wang Y . PPARs and the complex journey to obesity. Nat Med. 2004; 10(4):355-61. DOI: 10.1038/nm1025. View

15.

Forman B, Tontonoz P, Chen J, Brun R, Spiegelman B, Evans R . 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell. 1995; 83(5):803-12. DOI: 10.1016/0092-8674(95)90193-0. View

16.

Kliewer S, Lenhard J, Willson T, Patel I, Morris D, Lehmann J . A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation. Cell. 1995; 83(5):813-9. DOI: 10.1016/0092-8674(95)90194-9. View

17.

Kliewer S, Sundseth S, Jones S, Brown P, Wisely G, Koble C . Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc Natl Acad Sci U S A. 1997; 94(9):4318-23. PMC: 20720. DOI: 10.1073/pnas.94.9.4318. View

18.

Krey G, Braissant O, LHorset F, Kalkhoven E, Perroud M, Parker M . Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay. Mol Endocrinol. 1997; 11(6):779-91. DOI: 10.1210/mend.11.6.0007. View

19.

Nagy L, Tontonoz P, Alvarez J, Chen H, Evans R . Oxidized LDL regulates macrophage gene expression through ligand activation of PPARgamma. Cell. 1998; 93(2):229-40. DOI: 10.1016/s0092-8674(00)81574-3. View

20.

Nolte R, Wisely G, Westin S, Cobb J, Lambert M, Kurokawa R . Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma. Nature. 1998; 395(6698):137-43. DOI: 10.1038/25931. View