Philadelphia -- A group of Wistar Institute scientists working in the structural biology laboratory of Ronen Marmorstein, Ph.D., have identified a new mechanism by which proteins regulate DNA transcription.
Two articles, "Structure of a HAP1-DNA complex reveals dramatically asymmetric DNA binding by a homodimeric protein" and "Structure of HAP1-18-DNA complex suggests protein/DNA interactions have allosteric effects on transcription," which highlight their latest findings, appear in the January 1999 issue of the scientific journal, nature structural biology.
HAP1, a homodimeric protein, is a yeast transcriptional activator that binds to DNA. Unlike other homodimeric transcription factors that bind their DNA targets symmetrically, HAP1 adopts a drastically asymmetric conformation to recognize its target. "That," explains Dan King, co- author of the papers, "is an exception to the rule of proteins, which are usually very symmetrical. What this structure reveals is that homodimeric transcription factors can use asymmetry as a resourceful mechanism to recognize their DNA targets."
HAP1 has high homology with over 80 proteins in yeast. Although these proteins are from the same family, many have novel DNA recognition properties. By comparing HAP1 to other family members, Wistar's scientists are gaining information about how proteins recognize DNA targets.
Dr. Marmorstein's laboratory also has determined the structure of a mutant protein, HAP1-18, which binds normally to DNA but hyperactivates its target gene. "What we found," says King, "were conformational changes in the DNA binding domain and in the DNA itself that might explain how it affects activation of its target genes."
"These interactions," explains King, "are giving us important information about molecular recognition. Once we understand how each protein recognizes a particular DNA target, we will be able to develop proteins with unique DNA recognition properties potentially useful for drug design. That, however, is a long way off."
The Wistar Institute, established in 1892, was the first independent medical research facility in the country. For more than 100 years, Wistar scientists have been making history and improving world health through their development of vaccines for diseases that include rabies, German measles, infantile gastroenteritis (rotavirus), and cytomegalovirus; discovery of molecules like interleukin-12, which are helping the immune system fight bacteria, parasites, viruses and cancer; and location of genes that contribute to the development of diseases like breast, lung and prostate cancer. Wistar is a National Cancer Institute Cancer Center.