Article: New universe of miniproteins is upending cell biology and genetics

[Andy]

Mice put human runners to shame. Despite taking puny strides, the rodents can log 10 kilometers or more per night on an exercise wheel. But the mice that muscle biologist Eric Olson of the University of Texas Southwestern Medical Center in Dallas and colleagues unveiled in 2015 stood out. On a treadmill, the mice could scurry up a steep 10% grade for about 90 minutes before faltering, 31% longer than other rodents. Those iron mice differed from counterparts in just one small way—the researchers had genetically altered the animals to lack one muscle protein. That was enough to unleash superior muscle performance. "It's like you've taken the brakes off," Olson says.

Just as startling was the nature of the crucial protein. Muscles house some gargantuan proteins. Dystrophin, a structural protein whose gene can carry mutations that cause muscular dystrophy, has more than 3600 amino acids. Titin, which acts like a spring to give muscles elasticity, is the biggest known protein, with more than 34,000 amino acids. The protein disabled in the mice has a paltry 46. Although researchers have probed how muscles work for more than 150 years, they had completely missed the huge impact this tiny protein, called myoregulin, has on muscle function.

https://www.sciencemag.org/news/2019/10/new-universe-miniproteins-upending-cell-biology-and-genetics

 

[Forbin]

This is no doubt an unjustified leap, but I wonder if a miniprotein could be small enough to be a candidate for the the proverbial "something in the blood" ?

 

[Colin]

This is no doubt an unjustified leap, but I wonder if a miniprotein could be small enough to be a candidate for the the proverbial "something in the blood" ?

Mice can leap a long way... The smallest of these microproteins are around ten amino-acids long—the average for proteins being around 300—so I imagine that they're small enough.

That Science article doesn't go into the specifics of the recent Salk paper in Nature but the findings are even more interesting. The 54-amino-acid, PIGBOS microprotein that they've characterized is used to communicate with the mitochondria to help it with a stress response. Indeed, these small proteins seem to play helper roles in a variety of contexts so some might well circulate in the blood and might well have been overlooked.

For more on this fascinating field, see this Salk article:

"Going forward, we might consider how PIGBOS is involved in disease like cancer," says Chu. "In cancer patients, the ER is more stressed than in a normal person, so ER stress regulation could be a good target."

The researchers are interested in studying the roles of other mitochondrial proteins in ER stress, and in exploring how PIGBOS works in an animal model. The team is also forging ahead in characterizing the vast library of microproteins that may be crucial in cell biology.

"Microproteins represent a fledgling field," says Saghatelian. "But I think this work has really impacted our understanding the impact that microproteins can have on biochemistry and cell biology."

https://phys.org/news/2019-10-mysterious-microproteins-major-implications-human.html


And see also this Salk article on another microprotein, one called NoBody:

Part of the reason this molecule has been overlooked for so long, according to Saghatelian, is that no one knew NoBody existed. In addition, no one looked for microproteins because it was unclear whether any microproteins would have important functions. "The discovery of NoBody and its function in mRNA recycling suggests that at least some of the hundreds of other microproteins that we have found might also be functional, which is an exciting proposition," he says.

Slavoff adds, "The fact that NoBody has been present in this intensively studied complex of proteins all this time, but completely escaped our notice, really hammers home how many more currently unknown microproteins could be associated with essential cellular machineries."

https://phys.org/news/2016-12-microprotein-mission.html