Biochemical controls: circadian clock proteins (Introduction)

by David Turell , Tuesday, October 10, 2023, 19:39 (200 days ago) @ David Turell

They are on a 24-hour system:

https://www.quantamagazine.org/in-our-cellular-clocks-shes-found-a-lifetime-of-discover...

"This morning, when the sun came up, billions of humans opened their eyes and admitted into their bodies a shaft of light from space. When the stream of photons struck the retina, neurons fired. And in every organ, in nearly every cell, elaborate machinery stirred. Each cell’s circadian clock, a complex of proteins whose levels rise and fall with the sun, clicked into gear.

"That clock synchronizes our bodies to the light-dark cycle of the planet by controlling the expression of more than 40% of our genome. Genes for immune signals, brain messengers and liver enzymes, to name just a few, are all transcribed to make proteins when the clock says it’s time.

"That means you are not, biochemically, the same person at 10 p.m. that you are at 10 a.m. It means that evenings are a more dangerous time to take large doses of the painkiller acetaminophen: Liver enzymes that protect against overdose become scarce then. It means that vaccines given in the morning and evening work differently, and that night-shift workers, who chronically disobey their clocks, have higher rates of heart disease and diabetes.

***

"BMAL1 has a kind of waist that CLOCK clasps like a dancer. Each dawn, the pair take up perches on the densely coiled mass of the genome and summon the enzymes that transcribe DNA. Over the course of the day, they cause other proteins to whirl out of the cell’s machinery, including several that eventually eclipse their power. Three proteins find handholds on CLOCK and BMAL1 around 10 p.m., silencing them and stripping them from the genome. The tide of DNA transcription shifts. Finally, in the depths of night, a fourth protein grips a tag on the end of BMAL1 and prevents any further activation.

"Seconds turn into minutes, minutes into hours. Time passes. Gradually, the repressive quartet of proteins decays. In the small hours of the morning, CLOCK and BMAL1 are once again being made to renew the cycle.

"Every day of your life, this system links the body’s fundamental biology to the movement of the planet. Every day of your life, as long as it lasts.

***

"...she found that CRY1 silences BMAL1 by binding competitively to its wriggling, disordered tail; if the tail is mutated, the clock veers off tempo or even disintegrates completely. With her student Alicia Michael, she found that CLOCK nestles against CRY1 by threading a loop into a pocket on it; if a mutation destroys the pocket, the two won’t bind. A mutation in PER2 makes it fit less well against its binding partners and renders it vulnerable to degradation; that defect advances the clock by an hour and a half. The orientation of a single bond in the tail of BMAL1 can shorten the day. The pieces of the clockwork were starting to emerge from darkness.

***

"Her findings gave chronobiology a new view of how clock proteins work. “What Carrie has discovered over and over again is that a lot of the important biology comes from the parts of the proteins that are unstructured, highly flexible and dynamic,” said Andy LiWang of the University of California, Merced, a structural biologist who studies the clock in cyanobacteria. “What she’s doing with NMR is heroic.”

***

"He points out in the figure how PER2 is a mass of mostly disordered regions. “These are regions that are extremely important,” he says. Until Partch showed otherwise, “most people used to think disorder was the nonfunctional bits.” (my bold)
***

"Partch is thinking more and more these days about what is universal in life’s measurement of time. Some years ago, LiWang invited her to work with him on the clock in cyanobacteria, which has no parts in common with the human clock. It consists of just three proteins called KaiA, KaiB and KaiC, whose activity rises and falls in a 24-hour rhythm, and their two binding partners, which drive the translation of genes. In 2017 the team led by LiWang and Partch released detailed structures of each of the complexes, revealing the folds and twists that allow them to attach to each other. Later, the group showed that they could put the clock proteins into a test tube and get them to cycle for days, even months.

"They were deeply into recording how that cycle was driven when Partch recognized something she’d seen while studying the human clock: competition. The little tag where CRY1 binds to BMAL1 is also where one of BMAL1’s strongest activators binds. If CRY1 outcompetes that activator, taking its place on the tag, the clock can only go forward. It is locked into this process, waiting out the minutes and the hours until the CRY1 protein’s bond decays and the clock’s cycle begins again.

"In the cyanobacterial clock, Partch realized, competition among the components works the same way. It crops up, too, in the clocks of organisms like worms and fungi. “This seems to be a conserved principle in very, very different clocks,” she said. She wonders if it reflects a fundamental biophysical truth about how nature makes machines that march forward in time, following a path from which they cannot swerve.

Comment: the human thought pattern gets in the way. Note the bold. We cannot outthink God. All parts of all proteins are there for a reason, God's reasons. This is a shortened version of an interview with Dr. Carrie Partch.