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Molecular and Cellular Biology, January 2003, p. 238-249, Vol. 23, No. 1
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.1.238-249.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

LXXLL-Related Motifs in Dax-1 Have Target Specificity for the Orphan Nuclear Receptors Ad4BP/SF-1 and LRH-1

Taiga Suzuki,1,2 Megumi Kasahara,3 Hidefumi Yoshioka,3 Ken-ichirou Morohashi,1,4* and Kazuhiko Umesono2,5

Department of Developmental Biology, National Institute for Basic Biology, Okazaki 444-8585,1 Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto 606-8507,2 Department of Natural Sciences, Hyogo University of Teacher Education, Hyogo 673-1494,3 Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation, Kawaguchi 332-0012,4 Graduate School for Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan5

Received 5 April 2002/ Returned for modification 25 June 2002/ Accepted 24 September 2002

The orphan receptor Ad4BP/SF-1 (NR5A1) is a constitutive activator, and its activity is repressed by another orphan receptor, Dax-1 (NR0B1). In the present study, we investigated the molecular mechanisms underlying this repression by Dax-1. Yeast two-hybrid and transient-transfection assays confirmed the necessity of three LXXLL-related motifs in Dax-1 for interaction with and repression of Ad4BP/SF-1. In vitro pull-down experiments confirmed that Dax-1 interacts with Ad4BP/SF-1 and also with LRH-1 (NR5A2). The target specificity of the LXXLL-related motifs was indicated by the observations that Ad4BP/SF-1, ER{alpha} (NR3A1), LRH-1, ERR2 (NR3B2), and fly FTZ-F1 (NR5A3) interacted through their ligand binding domains with all the LXXLL-related motifs in Dax-1 whereas HNF4 (NR2A1) and ROR{alpha} (NR1F1) did not. Transcriptional activities of the receptors whose DNA binding domains (DBDs) were replaced by the GAL4 DBD were repressed by Dax-1 to various levels, which correlated with the strength of interaction. Amino acid substitutions revealed that Ad4BP/SF-1 and LRH-1 preferentially interact with L(+1)XXLL-related motifs containing serine, tyrosine, serine, and threonine at positions -2, +2, +3, and +6, respectively. Taken together, our results indicate that the specificities of LXXLL-related motifs in Dax-1 based on their amino acid sequences play an important role in regulation of orphan receptors.

* Corresponding author. Mailing address: Department of Developmental Biology, National Institute for Basic Biology, Myodaiji-cho, Okazaki 444-8585, Japan. Phone: 81-564-55-7560. Fax: 81-564-55-7561. E-mail: moro{at}nibb.ac.jp.

Molecular and Cellular Biology, January 2003, p. 238-249, Vol. 23, No. 1
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.1.238-249.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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