Turning genes on
The central dogma says that DNA goes to RNA goes to protein. While this sounds simple enough, it is far from it. The process by which the information in the DNA is converted into RNA known as transcription is a complicated one. It involves the basic transcription machinery, which includes the RNA polymerase, and many activators and coactivators. The activators enhance transcription and the coactivators bridge the activators to the general transcription machinery. The details of how these proteins function to stimulate transcription is not clear.
Now, Tom Alber and coworkers at the University of California, Berkeley, USA have determined how one activator-coactivator pair functions to stimulate transcription Nature Structural Biology (Vol 7, No. 9, September 2000). The activator they studied, hepatocyte nuclear factor-1a (HNF-1a), is an important regulator of genes in liver, kidney, stomach and pancreatic islet cells. In the test tube, when HNF-1a binds its coactivator (dimerization cofactor of HNF-1, also known as DCoH), transcription is enhanced.
Solving the three-dimensional structure of the complex by X-ray crystallography they showed that it is composed of two copies each of HNF-1a and DCoH (a 'dimer of dimers'). Previous work showed that isolated DCoH forms a tetramer (in which there are four copies of DCoH) in solution that is transcriptionally inactive. In the complex, HNF-1a binds to the same surface that typically mediates DCoH tetramer formation. Thus, formation of the inactive DCoH tetramer competes with formation of the active HNF-1a-DCoH complex. This mechanism of competition differs from more standard regulatory mechanisms in which conformationals changes alter the affinities of the proteins for one another.
Almost 100 human HNF-1a mutations have been associated with an inherited form of diabetes known as maturity-onset diabetes of the young type 3 (MODY3). The structure suggests how some of these mutations could reduce activator function. For example, mutations that inhibit the formation of the HNF-1a dimer would affect its interaction with DCoH, DNA binding and ultimately transcription. Thus, the structure of the DCoH-HNF-1a complex illustrates one way in which activators and coactivators can cooperate to stimulate transcription, and also how this process can be disrupted to cause disease.
Dr. Tom Alber
Department of Molecular and Cell Biology
229 Stanley Hall #3206
University of California, Berkeley
Tel: 510 642 8758
Fax: 510 643 9290
(C) Nature Structural Biology press release.
Message posted by: Trevor M. D'Souza