This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager NURSA Molecule Pages Link Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Andersin, T. Articles by Carlberg, C. Search for Related Content PubMed PubMed Citation Articles by Andersin, T. Articles by Carlberg, C.

The Critical Role of Carboxy-Terminal Amino Acids in Ligand-Dependent and -Independent Transactivation of the Constitutive Androstane Receptor

Department of Biochemistry, University of Kuopio, FIN-70211 Kuopio, Finland

Address all correspondence and requests for reprints to: Professor Carsten Carlberg, Department of Biochemistry, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland. E-mail: carlberg{at}messi.uku.fi.

The mouse constitutive androstane receptor (CAR) is a unique member of the nuclear receptor superfamily, for which an inverse agonist, the testosterone metabolite 5-androstan-3-ol (androstanol), and an agonist, the xenobiotic 1,4-bis[2-(3, 5-dichloropyridyloxy)] benzene, are known. In this study the role of the transactivation domain 2 (AF-2) of CAR was investigated, which is formed by the seven most carboxy-terminal amino acids of the receptor. The AF-2 domain was shown to be critical for the constitutive activity by mediating a ligand-independent interaction of CAR with coactivator (CoA) proteins. In addition this domain increased and decreased contact with CoAs in the presence of agonist and inverse agonist, respectively. In analogy to classical endocrine nuclear receptors, in CAR the charge clamp between K187 (in helix 3) and E355 (within the AF-2 domain) was expected to be critical for its interaction with CoAs. However, the hydrophobic amino acids L352, L353, and I356 on the surface of the AF-2 domain were found to be more important for this protein-protein interaction. Moreover, these amino acids and C357 were shown to be involved in the response of CAR to androstanol. Interestingly, the cysteine at position 357 appears to block classical endocrine responsiveness of CAR to agonists, since mutagenesis of this amino acid both reduced CoA interaction in the absence of ligand and drastically increased inducibility by 1,4-bis[2-(3, 5-dichloropyridyloxy)] benzene. We showed that this blockade is not due to an intramolecular disulfide bridge, but is probably caused by an interaction between C357 and Y336.

NURSA Molecule Pages Link:

Nuclear Receptors:   VDR  |  CAR

Coregulators:   GRIP1

Ligands:   Calcitriol  |  TCPOBOP  |  Androstanol

This article has been cited by other articles:

				M. T. Mizwicki and A. W. Norman The Vitamin D Sterol-Vitamin D Receptor Ensemble Model Offers Unique Insights into Both Genomic and Rapid-Response Signaling Sci. Signal., June 16, 2009; 2(75): re4 - re4. [Abstract] [Full Text] [PDF]

				L. Michalik, V. Zoete, G. Krey, A. Grosdidier, L. Gelman, P. Chodanowski, J. N. Feige, B. Desvergne, W. Wahli, and O. Michielin Combined Simulation and Mutagenesis Analyses Reveal the Involvement of Key Residues for Peroxisome Proliferator-activated Receptor{alpha} Helix 12 Dynamic Behavior J. Biol. Chem., March 30, 2007; 282(13): 9666 - 9677. [Abstract] [Full Text] [PDF]

				H. Lempiainen, F. Molnar, M. Macias Gonzalez, M. Perakyla, and C. Carlberg Antagonist- and Inverse Agonist-Driven Interactions of the Vitamin D Receptor and the Constitutive Androstane Receptor with Corepressor Protein Mol. Endocrinol., September 1, 2005; 19(9): 2258 - 2272. [Abstract] [Full Text] [PDF]

				F. Molnar, M. Matilainen, and C. Carlberg Structural Determinants of the Agonist-independent Association of Human Peroxisome Proliferator-activated Receptors with Coactivators J. Biol. Chem., July 15, 2005; 280(28): 26543 - 26556. [Abstract] [Full Text] [PDF]

				J. Xia and B. Kemper Structural Determinants of Constitutive Androstane Receptor Required for Its Glucocorticoid Receptor Interacting Protein-1-mediated Nuclear Accumulation J. Biol. Chem., February 25, 2005; 280(8): 7285 - 7293. [Abstract] [Full Text] [PDF]

				J. Jyrkkarinne, B. Windshugel, J. Makinen, M. Ylisirnio, M. Perakyla, A. Poso, W. Sippl, and P. Honkakoski Amino Acids Important for Ligand Specificity of the Human Constitutive Androstane Receptor J. Biol. Chem., February 18, 2005; 280(7): 5960 - 5971. [Abstract] [Full Text] [PDF]

				J. K. Lamba, V. Lamba, K. Yasuda, Y. S. Lin, M. Assem, E. Thompson, S. Strom, and E. Schuetz Expression of Constitutive Androstane Receptor Splice Variants in Human Tissues and Their Functional Consequences J. Pharmacol. Exp. Ther., November 1, 2004; 311(2): 811 - 821. [Abstract] [Full Text] [PDF]

				C. Frank, F. Molnar, M. Matilainen, H. Lempiainen, and C. Carlberg Agonist-dependent and Agonist-independent Transactivations of the Human Constitutive Androstane Receptor Are Modulated by Specific Amino Acid Pairs J. Biol. Chem., August 6, 2004; 279(32): 33558 - 33566. [Abstract] [Full Text] [PDF]

				K. Swales and M. Negishi CAR, Driving into the Future Mol. Endocrinol., July 1, 2004; 18(7): 1589 - 1598. [Abstract] [Full Text] [PDF]

				C. Handschin and U. A. Meyer Induction of Drug Metabolism: The Role of Nuclear Receptors Pharmacol. Rev., December 1, 2003; 55(4): 649 - 673. [Abstract] [Full Text] [PDF]

				M. M. Gonzalez, P. Samenfeld, M. Perakyla, and C. Carlberg Corepressor Excess Shifts the Two-Side Chain Vitamin D Analog Gemini from an Agonist to an Inverse Agonist of the Vitamin D Receptor Mol. Endocrinol., October 1, 2003; 17(10): 2028 - 2038. [Abstract] [Full Text] [PDF]