Biochemistry assistant professor Srivatsan “Vatsan” Raman has received a Director’s New Innovator Award from the National Institutes of Health (NIH). The $2.2 million-grants fund high-risk, high-reward research performed by early stage investigators. Compared to traditional NIH grants, the New Innovator Award supports “unusually creative early stage investigators” whose research can have a broad impact on biomedical sciences.
Raman’s project is focused on understanding protein allostery. Allostery is a property by which when something happens to one part of a protein, a signal is somehow communicated to another part of the protein, where another action takes place. This “long-distance” communication is called allostery.
“Allosteric proteins are nature’s switches,” explains Raman, who is also affiliated with the Department of Bacteriology and the Great Lakes Bioenergy Research Center. “The classical view, one that every biochemistry textbook follows, is that only some proteins exhibit allosteric properties. However, this view is dated. There is increasing recognition that allostery is a fundamental property of all proteins, just as folding is, and that allosteric behavior is more pronounced in some proteins than others. Allosteric proteins regulate many essential cellular processes required for life. They switch states from on to off or off to on and that’s how they turn on and off a very large number of genes. However, sometimes they acquire a mutation that causes the switch to be permanently on or off when it shouldn’t be. This dysfunction is responsible for many diseases, including cancer, because activities inside a cell are no longer regulated.”
Because of their central role in regulation, these proteins are popular drug targets. Raman says almost half of all current drug targets are allosteric proteins. Yet, little is understood about how allostery itself works.
“So, the thesis of this award is: how does this on/off business work?” Raman says. “Can we figure out the specific amino acids — the smaller units that make up proteins — that allow it to change between on and off? In my laboratory, we develop high throughput methods to probe the role of every amino acid in these proteins to decipher which are involved in allostery.”
Raman explains that their grand objective is to not just study allostery in one or two proteins, but understand the fundamental “rules” of the property. To achieve this, they plan to utilize their data from high throughput analysis experiments together with machine learning to look for commonalities across different allosteric proteins. Then the computer could look at an arbitrary allosteric protein with a mutation and predict the impact of that mutation and possibly how is best to alleviate any detrimental effects.
“The broader vision of my laboratory is to develop these tools to advance precision medicine,” Raman says. “Every day we sequence the genomes of patients with diseases, but we have no clue which protein mutations affect function, and how they do so. Wouldn’t it be great if we could create a ‘lookup table’ or a database of mutations that a physician could use to interpret a patient’s genome?
“Drug companies are also very interested in learning how allostery works,” Raman adds. “For example, most drugs target a protein’s active site to block its action. The problem is that many proteins have similar active sites so a drug that targets them can cause harmful side effects. By comparison, allosteric sites are much more specific and understanding them to be able to target them instead can lead us to better drugs. An example of this is an estrogen receptor involved in breast cancer.”
The award is funded by the NIH Common Fund, which supports a series of high-impact programs across the NIH. The New Innovator Award was established in 2007 and supports innovative research from early career investigators who are within 10 years of their final degree or clinical residency. Two other faculty at UW–Madison also received the award: assistant professor of neuroscience Darcie Moore and professor of medicine Nasia Safdar.
Raman’s award is supported by the NIH Common Fund, grant number DP2 GM132682.