Defining requirements for heterodimerization between the retinoid X receptor and the orphan nuclear receptor Nurr1

Piia Aarnisalo, Chae Hee Kim, Jae Lee, Thomas Perlmann

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

Nurr1, an orphan nuclear receptor mainly expressed in the central nervous system, is essential for the development of the midbrain dopaminergic neurons. Nurr1 binds DNA as a monomer and exhibits constitutive transcriptional activity. Nurr1 can also regulate transcription as a heterodimer with the retinoid X receptor (RXR) and activate transcription in response to RXR ligands. However, the specific physiological roles of Nurr1 monomers and RXR-Nurr1 heterodimers remain to be elucidated. The aim of this study was to define structural requirements for RXR-Nurr1 heterodimerization. Several amino acid substitutions were introduced in both Nurr1 and RXR in the I-box, a region previously shown to be important for nuclear receptor dimerization. Single amino acid substitutions introduced in either Nurr1 or RXR abolished heterodimerization. Importantly, heterodimerization-deficient Nurr1 mutants exhibited normal activities as monomers. Thus, by introducing specific amino acid substitutions in Nurr1, monomeric and heterodimeric properties of Nurr1 can be distinguished. Interestingly, substitutions in the RXR I-box differentially affected heterodimerization with Nurr1, retinoic acid receptor, thyroid hormone receptor, and constitutive androstane receptor demonstrating that the dimerization interfaces in these different heterodimers are functionally unique. Furthermore, heterodimerization between RXR and Nurr1 had a profound influence on the constitutive activity of Nurr1, which was diminished as a result of RXR interaction. In conclusion, our data show unique structural and functional properties of RXR-Nurr1 heterodimers and also demonstrate that specific mutations in Nurr1 can abolish heterodimerization without affecting other essential functions.

Original languageEnglish (US)
Pages (from-to)35118-35123
Number of pages6
JournalJournal of Biological Chemistry
Volume277
Issue number38
DOIs
StatePublished - Sep 20 2002
Externally publishedYes

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Nuclear Receptor Subfamily 4, Group A, Member 2
Retinoid X Receptors
Substitution reactions
Amino Acid Substitution
Dimerization
Monomers
Transcription
Amino Acids
Thyroid Hormone Receptors
Retinoic Acid Receptors
Dopaminergic Neurons
Neurology
Cytoplasmic and Nuclear Receptors
Mesencephalon
Neurons

ASJC Scopus subject areas

  • Biochemistry

Cite this

Defining requirements for heterodimerization between the retinoid X receptor and the orphan nuclear receptor Nurr1. / Aarnisalo, Piia; Kim, Chae Hee; Lee, Jae; Perlmann, Thomas.

In: Journal of Biological Chemistry, Vol. 277, No. 38, 20.09.2002, p. 35118-35123.

Research output: Contribution to journalArticle

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