AMHERST —For a decade, University of Massachusetts researchers Margaret Stratton and Eric Strieter have been locked in a friendly rivalry over whose protein is more important.
Stratton champions a memory-related enzyme called calcium-dependent protein kinase II (CaMK II), while Strieter favors a family of regulatory proteins called ubiquitin.
The debate took a turn when Johnathon Lipton, a researcher at Boston Children’s Hospital, discovered that a protein tied to the body’s circadian clock — Basic helix-loop-helix ARNT-like protein 1, or BMAL1 — interacts with both Stratton’s and Strieter’s molecules. That finding led the three researchers to hypothesize that CaMK II, ubiquitin and BMAL1 may work together in a cycle, forming a separate internal clock connected to memory and sleep.
Now, a $1.3 million grant will let them find out whether an undiscovered second internal clock may govern memory and sleep.
With the three-year grant from the W. M. Keck Foundation, Stratton, Strieter and Lipton will test that hypothesis in what could be a breakthrough in understanding mammal biology.
“This would be a totally new idea,” said Stratton, a professor in the Department of Biochemistry and Molecular Biology. “There aren’t a bunch of other clocks that are working that we know of.”
The only known internal timer in mammals is the circadian clock. Synchronized with the 24-hour cycle of the sun, circadian rhythms communicate when it is time to eat or sleep, but also affect hormones, appetite and body temperature.
The array of essential biological functions relying on this clock may be too much for one internal timer to handle, which is where this undiscovered second clock comes in, Stratton and Strieter said. It likely regulates energy-intensive tasks on a shorter schedule, particularly in relation to memory recall and storage.
While this smaller, internal clock operates separately, the involvement of BMAL1 hints at a potential connection between this new clock and its famous canonical counterpart, said Strieter, a chemistry professor.
Natural history provided a model for the potential clock. Ancient cyanobacteria, the first known organisms to produce oxygen, contained a similar regulatory timer. One of the proteins in this clock, KaiC, looks a lot like CaMK II.
“There’s a lot of hallmarks reminiscent of that clock, including the way CaMK II looks and behaves, and then how that clock is internally regulated,” Stratton said.
The clock not only informs bodily activity, but could link human diseases to time. Blood pressure, heart failure and diabetes have all been tied to BMAL1 mutations and disruptions. Too little of CaMK II can lead to impaired memory and motor skills, but too much can result in seizures. In one study, too much CaMK II activity proved lethal in fruit flies.
“It’s a bit of a Goldilocks,” Stratton said.
While the mechanisms of this clock remain unknown, the three researchers have already begun learning what makes this clock tick through their previous work. Stratton and Strieter have spent several years documenting the way ubiquitin keeps CaMK II at bay.
“We ended up finding the components of the ubiquitin proteasome system that were specifically regulating CaMK II, and so that’s kind of where the story of this clock begins,” Strieter said.
But BMAL1 involvement is entirely new and will require several years of study to fully map out. Still, when Lipton told Stratton about BMAL1 interacting with CaMK II, his observation made sense — previous studies have found that disruptions of CaMK II activity can decrease sleep.
“Our role is going to be taking our current system of two proteins and now adding in the third protein to see how that affects what we’ve already learned,” Stratton said.
The research process begins by investigating interactions between each protein, then proving these encounters are cyclical. At UMass, Stratton and Strieter will observe how CaMK II, ubiquitin and BMAL1 change through photographs and enzyme assays, a technique for measuring enzyme activity. In Boston, Lipton will monitor mouse brain activity to connect any lab findings to mammal circadian rhythms.
Together, they will find what makes this clock, and by extension humans, tick.
