Identification of functional surfaces of the zinc binding domains of intracellular receptors.
Transcriptional regulatory factor complexes assemble on genomic response elements to control gene expression. To gain insights on the surfaces that determine this assembly in the zinc binding domains from intracellular receptors, we systematically analyzed the variations in sequence and function of those domains in the context of their invariant fold. Taking the intracellular receptor superfamily as a whole revealed a hierarchy of amino acid residues along the DNA interface that correlated with response element binding specificity. When only steroid receptors were considered, two additional sites appeared: the known dimer interface, and a novel putative interface suitably located to contact regulatory factors bound to the free face of palindromic response elements commonly used by steroid receptors. Surprisingly, retinoic acid receptors, not known to bind palindromic response elements, contain both of these surfaces, implying that they may dimerize at palindromic elements under some circumstances. This work extends Evolutionary Trace analysis of functional surfaces to protein-DNA interactions, suggests how coordinated exchange of trace residues may predictably switch binding specificity, and demonstrates how to detect functional surfaces that are not apparent from sequence comparison alone.
Lichtarge
O
O
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143-0450, USA.
Yamamoto
K R
KR
Cohen
F E
FE
D000595:Amino Acid Sequence; D001665:Binding Sites; D017124:Conserved Sequence; D004247:DNA / Q000378:metabolism; D019281:Dimerization; D019143:Evolution, Molecular; D008958:Models, Molecular; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D011987:Receptors, Steroid / Q000737:chemistry / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism; D015032:Zinc / Q000737:chemistry / Q000378:metabolism*
D011506:Proteins; D011987:Receptors, Steroid; D014157:Transcription Factors; D004247:DNA; D015032:Zinc