Biochemistry – proteins constitute the gliders of the work of cells. If they become overzealous, some enzymes give them the kiss of Judas, as it were: they receive a sign to which they submit to disposal.
Researchers in Vienna have deciphered the structure of this enzyme (HUWE1) and shown how it releases a large number of unwanted proteins for degradation: the snake-like molecule thus has a very promising therapeutic potential, according to the researchers in the journal Nature Chemical Biology.
Cells balance their functional proteins with the help of a group of enzymes called “ubiquitin ligases”. Just as a member of a mafia clan with Paseo della Mort is set to die by the Godfather, unwanted proteins receive a ubiquitin label from these QCs. If other enzymes in the cell recognize this sign, they destroy the protein in question before it can harm the cell.
Science is interested in these ubiquitin gasses because – appropriately reprogrammed – they can identify disease-causing proteins for degradation. But first you need to understand exactly how it works. The problem is in the sheer size of these enzymes, which makes them difficult to study.
HUWE1 – Beneficial Monster Enzyme
The team of Tim Clausen of the Institute for Research Molecular Pathology (IMP) in Vienna and Dirk Kessler of the pharmaceutical company Boehringer Ingelheim have now succeeded in deciphering the structure and mode of operation of the ubiquitin ligase HUWE1. HUWE1 is a generalist with a wide range of target proteins, which is why it holds great promise for potential therapeutic applications. It also plays an important role in marking proteins for degradation during cancer development.
It turns out that HUWE1 binds to its targets in an unusual way. Unlike many other ubiquitin ligases, which have few binding sites to bind to specific proteins, HUWE1 always has a large number of such binding sites. These are lined up in a long, dynamic vortex that gives the massive enzyme a snake-like appearance.
“If we can elucidate the molecular details that underlie target selectivity, we may be able to target a wide range of disease-causing proteins,” Clausen said in a press release. In the next step, the researchers want to develop small synthetic molecules that “stick” HUWE1 to proteins that must be destroyed. This can remove unwanted disease-causing proteins from the cell.
* Technical publication link http://dx.doi.org/10.1038/s41589-021-00831-5