Credit: Karolinska Institutet
In a study published in Nature Structural and Molecular Biology, scientists from the Department of Medical Biochemistry and Biophysics at Karolinska Institutet, have discovered that water molecules play a crucial role in helping proteins, specifically transcription factors, read and regulate the human genome.
Only approximately 1% of our genome consists of genes, sections of DNA that specify the structure and function of proteins. Protein-coding genes are highly similar among mammals, with most differences between humans and other animals arising from how gene activity is regulated.
Proteins called transcription factors regulate gene activity so that only a necessary set of genes is switched on at a particular place and time. Each transcription factor recognizes and binds to a unique short DNA sequence, most often located in the 99% of the genome that does not encode proteins. Binding of transcription factors either increases or decreases the expression of nearby genes.
"How a transcription factor chooses its binding site has been a long-standing question in biology. By combining high-resolution structural analysis with advanced computational methods, we have unveiled that water, which forms the bulk of the cell mass, helps transcription factors bind to DNA and distinguish between closely related DNA sequences," says Ekaterina Morgunova, corresponding author and researcher in Jussi Taipales Group at Karolinska Institutet.
The research team discovered that the same transcription factor can bind to two different DNA sequences, each time utilizing water but differently: for one sequence, water molecules helped bind because they were liberated to move freely, increasing disorder (entropy). For another sequence, water molecules "froze" between the transcription factor and DNA, bridging the two.
"Understanding the mechanisms of interactions between transcription factors and DNA is essential to understanding normal gene regulation, how it changes during disease, and how gene regulation can be manipulated for therapy. The results provide crucial information for understanding mechanisms of gene regulation," says Morgunova.
The study used a combination of high-throughput technologies (SELEX) for finding the specific DNA sequences bound by transcription factors, high-resolution X-ray crystallography for solving structures of transcription factors bound to DNA, and advanced simulation techniques, including the Per|Mut algorithm for the quantification of the effect of disorder (entropic contribution) of the water molecules at the protein-DNA interface.
"This study is part of a multidisciplinary investigation in our lab and our goal is to fully decode the regulatory grammar of our genome, to explain how DNA sequence determines when and where genes are expressed, and how variants and mutations that cause disease alter gene expression," says Morgunova.
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