Mutations in the Glucocorticoid Receptor DNA-binding Domain Mimic an Allosteric Effect of DNA

Abstract

Introduction The expression of genetic information is governed largely by sequence-specic DNA-binding proteins that activate or repress transcription by RNA polymerase. Although these proteins commonly contain discrete DNA-binding and transcriptional regulatory domains that can be separated articially, experimental evidence suggests that in some regulatory proteins these domains communicate with each other to operate as integrated units (Lefstin & Yamamoto, 1998). Examples of such proteins are found in the intracellular receptors, an extensive superfamily of transcriptional regulatory proteins that is represented in all metazoans. Members of this superfamily are characterized by a conserved DNA-binding domain (DBD) with two zinc ions each coordinated by four cysteine residues. Although some intracellular receptor superfamily members bind DNA as monomers, most known members bind to DNA sites as homodimers, heterodimers with another superfamily member, or in conjunction with unrelate