Maillard Paper Named Editor's Pick
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Chemistry professor Rodrigo Maillard’s paper was named an Editor’s Pick in聽the聽Journal of Biological Chemistry聽this month. Third-year Ph.D student聽Sahar聽Foroutannejad created this accompanying illustration, which depicts the protein at the center of the study.
April 10, 2016 鈥�聽When chemistry professor Rodrigo Maillard鈥檚 manuscript was selected as an Editor鈥檚 Pick at the prestigious this month, it meant聽more to the 3rd-year professor than just a big splash for his lab.
Maillard had conceived of the idea behind this paper 鈥� the first from the at Georgetown 鈥� as a graduate student at the University of Texas Medical Branch in 2003. It wasn鈥檛 until this past year that he had the resources to try it.
鈥淎symmetric Configurations in a Reengineered Homodimer Reveal Multiple Subunit Communication Pathways in Protein Allostery鈥� describes a new finding on the behavior of mutations in a protein in the bacteria Escherichia coli. Essentially, Maillard sought to understand whether the behavior of negative-dominant mutations 鈥� proteins where mutations in only part of the structure lead the entire protein to malfunction 鈥斅燾ould be manipulated to improve their function.
The answer? Yes 鈥斅燽ut it鈥檚 complicated.
Maillard and his team created a protein chimera, a lab-engineered hybrid that imitates the behavior of real-life proteins but can be precisely manipulated by researchers. They attempted to change the protein鈥檚 behavior by changing the proportion of 鈥済ood鈥� structure to 鈥渂ad鈥� structure, and in doing so discovered that the reality of negative-dominant mutations is more nuanced than scientists previously believed.
鈥淲e can assess in a very controlled fashion how the entire chimera behaves,鈥� Maillard said.
The Georgetown team studies many combinations of functional and nonfunctional protein parts, experimenting with different mutations to assess the effects on the protein鈥檚 overall function.
Engineering mutations that enhance function, it seems, can make the protein behave better than it did before, even though the overall effect is still not an optimally functioning protein. While the mutated (bad) effect still dominates, the idea that this process can operate on a spectrum 鈥� rather than any mutated genes dooming the protein 鈥斅爄s a new revelation.
鈥淚magine you have five positive protein parts and five negative parts,鈥� Maillard said. 鈥淚ntuitively, if you mix them, you鈥檇 expect the molecule to be neutral. It鈥檚 not 鈥斅爄t鈥檚 still negative. But the 鈥榙ominant negative effects鈥� don鈥檛 truly dominate when you have a hyperactive positive component. The positive component would 鈥榬escue鈥� it, at least a little bit.鈥�
Maillard鈥檚 discovery came as the result of constant, painstaking work. It took his team over a year of trial-and-error protein manipulation, with few signs of whether they were on the right track.
鈥淣ature has done things for a certain reason,鈥� Maillard said. 鈥淔orcing it to be a way it doesn鈥檛 want to be鈥t takes a lot of back-and-forth. And you don鈥檛 know if you鈥檙e 10 miles away or 100 yards away.鈥�
Plans for further research on the topic include examining why negative-dominant mutations tend to dominate over positive ones, and whether adding positive mutations or drugs that enhance activity of good parts pushes the protein closer to full function. A more ambitious goal is to directly study mutant proteins that are related to cancer cells 鈥斅爌53, for example, a cell division-regulating protein whose malfunction is associated with cancerous growth.
鈥淚t鈥檚 a very complex protein,鈥� Maillard said. 鈥淚magine we鈥檙e working with a simple one-level house 鈥� this would be a mansion. But that鈥檚 where we would like to go.鈥�
Still, Maillard is excited that his unique approach has landed his lab a spot in the Journal of Biological Chemistry.
鈥淚t鈥檚 a big honor,鈥� Maillard said. 鈥淚t鈥檚 humbling that very established people are seeing that the work coming from our lab is important.鈥�