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Orphan nuclear receptor NGFI-B forms dimers with nonclassical interface

¹ Instituto de Física de São Carlos, Departamento de Física e Informática, Universidade de São Paulo, CEP 13566-590 São Carlos, São Paulo, Brazil
² Laboratório de Biologia Estrutural e Zooquímica, CEIS, Universidade Estadual de São Paulo, CEP 13500-230 Rio Claro, Brazil
³ Laboratório de Expressão Gênica, Departamento de Bioquímica, Universidade Federal de Santa Catarina, 88040-900 Florianópolis, São Carlos, Brazil
⁴ Unité d'Expression des Genes Eucaryotes, Institut Pasteur, 75015 Paris, France

(RECEIVED November 28, 2006; FINAL REVISION April 21, 2007; ACCEPTED May 1, 2007)

The orphan receptor nerve growth factor-induced B (NGFI-B) is a member of the nuclear receptor's subfamily 4A (Nr4a). NGFI-B was shown to be capable of binding both as a monomer to an extended half-site containing a single AAAGGTCA motif and also as a homodimer to a widely separated everted repeat, as opposed to a large number of nuclear receptors that recognize and bind specific DNA sequences predominantly as homo- and/or heterodimers. To unveil the structural organization of NGFI-B in solution, we determined the quaternary structure of the NGFI-B LBD by a combination of ab initio procedures from small-angle X-ray scattering (SAXS) data and hydrogen–deuterium exchange followed by mass spectrometry. Here we report that the protein forms dimers in solution with a radius of gyration of 2.9 nm and maximum dimension of 9.0 nm. We also show that the NGFI-B LBD dimer is V-shaped, with the opening angle significantly larger than that of classical dimer's exemplified by estrogen receptor (ER) or retinoid X receptor (RXR). Surprisingly, NGFI-B dimers formation does not occur via the classical nuclear receptor dimerization interface exemplified by ER and RXR, but instead, involves an extended surface area composed of the loop between helices 3 and 4 and C-terminal fraction of the helix 3. Remarkably, the NGFI-B dimer interface is similar to the dimerization interface earlier revealed for glucocorticoid nuclear receptor (GR), which might be relevant to the recognition of cognate DNA response elements by NGFI-B and to antagonism of NGFI-B–dependent transcription exercised by GR in cells.

Keywords: orphan nuclear receptor; NGFI-B; glucocorticoid nuclear receptor; hydrogen–deuterium exchange; SAXS

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