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Researchers develop method to find new molecules that mediate chemical communication

By using patterns observed in some well-known signaling molecules, new research from Stanford mines genome sequences to identify new signaling peptides.

All thirty-six trillion of our cells use one language to communicate: chemistry. They send chemical signals back and forth to keep each other informed about what is happening elsewhere in the body and to coordinate a response. While these messenger molecules are essential for bodily functioning, scientists have only just begun to crack the molecular code of this chemical language.  

Discovering new components of this chemical language has historically been laborious and time consuming. However, researchers at Stanford have devised a way to identify many new potential communication molecules at once, much more quickly than with classical methods. This method, as well as two new molecules discovered with this pipeline, are described in a paper published in December 2023 in Nature Communications. 

“When people think about how cells talk to one another, everyone always defaults to the same set of molecules,” says Jon Long, Sarafan ChEM-H Institute Scholar and assistant professor of pathology, and senior author of the study. “But the chemical universe is much, much larger than just a restricted set of molecules”. 

3D structure of TRH protein
3D structure of TRH protein | Image credit: Jon Long

One of the best studied signaling molecules in this chemical language is called thyrotropin-releasing hormone, or TRH. TRH is a short protein, or peptide, that plays a key role in coordinating the hormones that regulate our pituitary and thyroid glands. Researchers have investigated various aspects of this molecule since its discovery in 1969 that won the Nobel Prize in Medicine and Physiology in 1977, but Long and Amanda Wiggenhorn, a graduate student in his lab, were interested in something that hadn’t garnered much attention before: the very ends. 

At either end of a TRH molecule you can find small chemical tweaks that are added after the peptide is made. These types of modifications are added to all sorts of proteins, but the specific combination of the two chemical “caps” found on TRH are unique to signaling molecules. 

“What's important is that these caps seem to be really restricted to signaling molecules. They're not on random proteins,” says Long. To identify new signaling molecules, Long and Wiggenhorn reasoned, they could search for these caps in otherwise overlooked chemicals in the body. 

These caps can only be added to certain combinations of amino acids, the building blocks of peptides. Wiggenhorn, a chemistry graduate student and a fellow in the Sarafan ChEM-H Chemistry/Biology Interface (CBI) Training Program, searched through the human and mouse genomes for other peptides where these amino acid sequences appear together at either end. Wiggenhorn identified hundreds of peptides with these caps, but she needed to test which, if any, of these were chemical signals used by our cells.  

To test this, first Wiggenhorn looked to see which of these predicted molecules could be found in the body. To do this, she searched for each predicted capped peptide in blood samples and used a synthetic version as a reference to match against. In humans and in mice, a total of 45 and 39 of these peptides, respectively - about 17-18% of the capped peptides predicted from each genome - were actually found in the blood.

Wiggenhorn next wanted evidence that these molecules are involved in communication. The authors did this by putting mice through a series of tests that should result in changes in their physiology, like exercise or changes in diet, and then measured the amount of these peptides before and after the tests. The authors found that all their capped peptides either increased or decreased in concentration in response to at least one test, supporting the idea that they are helping the body to communicate about how to respond to physiological changes. 

A few of their newly identified chemical signals in particular stood out.  The first is called CAP-TAC1. CAP-TAC1 was of interest because it is a chemical cousin of signaling molecules called tachykinins, which are molecules involved in many essential bodily functions like muscle contraction and neuron firing. Given its similarity to the tachykinins, Wiggenhorn and Long thought that CAP-TAC1 might be a new molecule with some similar properties. They found that CAP-TAC1 is similar in some ways to these other molecules because it is able to bind the same targets, but excitingly it also has unique properties unlike any of the other tachykinins. The Long lab is working to figure out what the implications of these new properties may be. 

The second capped peptide they explored is called CAP-GDF15.  Wiggenhorn found that mice injected with CAP-GDF15 consumed much less food than other mice. But how CAP-GDF15 affects hunger is still a mystery. “We don’t know what pathway it goes through,” said Wiggenhorn. “It’s potentially a new pathway, which I found really exciting.” 

Through this work, Wiggenhorn and Long have dramatically decreased the time it takes to discover new signaling molecules. And while they focused on the specific types of caps found in TRH, they think this method can be applied to other chemical caps. 

“Maybe we’re missing a lot of signaling peptides based on not knowing what we’re looking for,” said Wiggenhorn. “Predicting where these interesting modifications could be may lead us to new peptides that had never been predicted or thought about before.” This work opens the door for scientists to learn many new words in this language of chemical communication. 

Long is a member of Stanford Bio-X, the Stanford Cardiovascular Institute, the Wu Tsai Human Performance Alliance, the Maternal & Child Health Research Institute (MCHRI), the Diabetes Research Center, and the Wu Tsai Neurosciences Institute.

Other co-authors include Hind Abuzaid, Laetitia Coassolo, Veronica Li, Julia Tanzo, Wei Wei, Xuchao Lyu, and Katrin Svensson.

The work was supported by the National Institutes of Health, the Ono Pharma Foundation, and the Wu Tsai Human Performance Alliance.