IDENTIFICATION OF FUNCTIONAL SURFACES OF THE ZINC-BINDING DOMAINS OF INTRACELLULAR RECEPTORS

Transcriptional regulatory factor complexes assemble on genomic respon se elements to control gene expression To gain insights on the surface s that determine this assembly in the zinc binding domains from intrac ellular receptors, we systematically analyzed the variations in sequen ce and function of those domains in the context of their invariant fol d. Taking the intracellular receptor superfamily as a whole revealed a hierarchy of amino acid residues along the DNA interface that correla ted with response element binding specificity. When only steroid recep tors were considered, two additional sites appeared: the known dimer i nterface, and a novel putative interface suitably located to contact r egulatory factors bound to the free face of palindromic response eleme nts commonly used by steroid receptors. Surprisingly, retinoic acid re ceptors, not known to bind palindromic response elements, contain both of these surfaces, implying that they may dimerize at palindromic ele ments under some circumstances. This work extends Evolutionary Trace a nalysis of functional surfaces to protein-DNA interactions, suggests h ow coordinated exchange of trace residues may predictably switch bindi ng specificity, and demonstrates how to detect functional surfaces tha t are not apparent from sequence comparison alone. (C) 1997 Academic P ress Limited.