The Hinge Region as a Key Regulatory Element of Androgen Receptor Dimerization DNA Binding and Transactivation
Abstract
The androgen receptor binds direct repeats as well as inverted repeats of the 5'-AGAACA-3' core element. This makes this receptor unique in the family of nuclear receptors. The inverted repeats are called canonical AREs, the direct repeats selective AREs. In collaboration with the group of Daniel Gewirth (DAMDl7-01-1-0050) we were able to solve the crystal structure of the AR DNA binding domain bound to a direct repeat. The data indicate a stronger dimerization interface between the two AR protomers bound to the direct repeat in a unexpected head-to-head conformation. We are currently verifying the implication of several residues in this dimerization. A carboxyterminal extension of the DNA binding domain of the AR is known to be involved in DNA binding (unfortunately its structure remains unsolved), in nuclear localization and in transactivation control. We have identified an inhibitory region partially overlapping the nuclear localization signal. Surprisingly, deletions which affect DNA binding negatively have a positive effect on transactivation when tested in full size receptors. Mutating the acetylation sites does not affect this phenomenon. The deletion of the inhibitory region affects the MG132 (protease inhibitor) effects on transactivation. We are continuing the structure-function analysis of this region, and try to unravel the mechanism of potentiation of transactivation.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2004
- Accession Number
- ADA427188
Entities
People
- Frank A. Claessens