DNA-induced conformational changes are the basis for cooperative dimerization by the DNA binding domain of the retinoid X receptor

Dimerization of the DNA-binding domains of nuclear hormone receptors occurs in a manner that is highly cooperative with DNA binding. We have investiga ted the molecular basis for this cooperativity through an NMR study of the interaction between the monomeric DNA-binding domain (DBD) of the retinoid- X-receptor (RXR) and a single DNA half-site. Major changes were observed in the chemical shifts of the backbone resonances and in the pattern of mediu m-range nuclear Overhauser enhancement connectivities of the RXR upon bindi ng to DNA, indicating that the DNA induces conformational changes in the mo nomer. Binding to DNA induces and stabilizes the structure in a region of t he second zinc binding domain that forms the dimerization interface when RX R binds as a dimer to a direct repeat recognition element. These studies pr ovide direct experimental evidence that DNA-induced protein conformational changes constitute the molecular basis for cooperative enhancement of dimer formation and DNA binding by the nuclear hormone receptor DBDs. In contras t to the localized folding induced in the dimerization interface, DNA bindi ng leads to unfolding of the C-terminal helix found in the free RXR DBD. Un winding of this helix may facilitate homodimer formation by maximizing inte ractions between the two DNA-bound RXR domains. (C) 1998 Academic Press.