STRUCTURE AND FUNCTION OF THE GLUCOCORTICOID RECEPTOR

Glucocorticoids cause changes in the expression of target genes via in teraction with an intracellular receptor protein, the glucocorticoid r eceptor. This signal transduction process can be divided into a number of steps, each of which represents a functional facet of the receptor protein. These steps include (i) receptor transformation to an active form resulting from specific interaction with glucocorticoid steroid hormones, (ii) homo-dimerization, (iii) DNA-binding to specific hormon e response elements in the genome and (iv) modulation of the expressio n levels of linked genes. These aspects of glucocorticoid receptor fun ction have been studied using a combination of tertiary structure dete rmination, biochemical assays and a genetic approach using a yeast sys tem to screen for mutant receptors that are altered in function. The r esults show that contacts involving both the DNA and steroid binding d omains are involved in dimerization and high affinity DNA binding. Gen etic experiments have illuminated the role of amino acids within the r ecognition helix of the DNA-binding domain in discriminating between c ognate DNA response elements for the glucocorticoid receptor and close ly related binding sites for other nuclear receptors. Squelching exper iments suggest that the N-terminal transactivation domain of the recep tor contacts components of the general transcriptional machinery that appear to be distinct from the TATA binding protein, TFIID, during tra nsactivation of gene expression by the DNA-bound receptor.