The microprotein in the mitochondria (green) and in the nucleus (blue) was overexpressed in human cells. The yellow and pink areas show that the signal of the microprotein overlaps with the mitochondrial and nuclear signals. Credit: Clara Sandmann, Max Delbrück Center
Key points:
- In the past, scientists overlooked a particular class of tiny proteins thought to only exist in primates.
- Bioinformatic gene analyses revealed that existence of human “microproteins,” which developed millions of years later in the evolutionary process.
- Despite their age, the researchers found the “new” proteins can speak to the “old” proteins with no complications.
Our cells and tissues are bustling with millions of molecules, hormones, and other biomolecules. Some of the smallest organisms play a key role in many of the processes occurring in our bodies. Despite this knowledge, biologists and physicians have often overlooked a particular class of tiny proteins thought to only exist in primates.
A few years ago, discoveries made by Norbert Hübner and Sebastiaan van Heesch changed this view. Now, in a paper published in Molecular Cell, the researchers describe what they’ve learned about the miniproteins.
“We were able to show which genome sequences the proteins are encoded in, and when DNA mutations occurred in their evolution,” explains Jorge Ruiz-Orera, an evolutionary biologist in Hübner’s lab and one of the paper’s three lead authors.
Ruiz-Orera’s bioinformatic gene analyses revealed that unlike more frequently studied larger proteins, human microproteins developed millions of years later in the evolutionary process, but the huge age gap doesn’t appear to prevent the proteins from “talking” to each other. In fact, microproteins play a key role in a variety of cellular functions.
The researchers synthesized miniproteins on a membrane and then incubated them with a solution containing most of the proteins known to exist in a human cell. A sophisticated computer-aided analysis then allowed the researchers to identify individual binding pairs. The experiments confirmed the assumption that the microproteins “could influence cellular processes that are millions of years older than itself.”
Unlike the old, known protein, most microproteins emerged more or less “out of nowhere—in other words, out of DNA regions that weren’t previously tasked with producing proteins,” says Ruiz-Orera. Microproteins, therefore, didn’t take the conventional and much easier route of being copied and derived from existing versions. And because these small proteins only emerged during human evolution, they are missing from the cells of most other animals, such as mice, fish and birds. These animals, however, have been found to possess their own collection of young, small proteins.
During their work, the researchers also discovered the smallest human proteins identified to date—over 200 super-small proteins, all of which are smaller than 16 amino acids.
While the latest study investigated 281 microproteins, the team now intendeds to expand their experiments to include many more of the 7,000 recently cataloged microproteins in the hopes this will reveal as-yet-undiscovered functions.