The proteins help cells recognise other proteins that need to be removed or have their activity, location or interactions with other molecules regulated. The researchers also analysed how variants in the genes encoding these receptors may translate into disease symptoms.

Their review paper was published in Trends in Cell Biology.

A properly functioning cell constantly monitors its proteins, removing worn-out or unwanted ones while also regulating the activity and location of others. The ubiquitin-proteasome system plays an important role in this process.

Its enzymes mark selected proteins with ubiquitin, which acts as a molecular label. Depending on the type of marking, the protein may be targeted for degradation by the proteasome, the cellular 'shredder', or otherwise regulated.

Cullin–RING ligases constitute the largest family of RING E3 enzymes that assign these markings. The precision of their action is determined by substrate receptors, which recognise the specific proteins that the ligase will process.

When the gene encoding such a receptor is altered, this precise protein-control system can malfunction. The cell may remove the wrong proteins, fail to degrade proteins it should remove, or experience disruptions in other processes crucial to its function.

As a result, a single mutation can cause disruptions in brain development, muscle function, or the functioning of multiple organs. Such mechanisms may be behind some rare diseases.

The IIMCB researchers combined data on receptor function, tissue expression and associations with different types of disease.

They found that neurodevelopmental and neuromuscular symptoms are particularly common among diseases linked to these receptors, even though most of the receptors do not show clearly tissue-specific expression.

Their analyses therefore indicate that clinical presentation cannot be explained solely by where the proteins are expressed. Other factors may include the substrates the receptors recognise, gene activity at different stages of development, the vulnerability of particular cell types, gene dosage and the effect of a specific variant on the function of the entire cullin–RING ligase complex.

'This resource can serve as a reference point for research into rare diseases and the ubiquitin–proteasome system. It can help identify further potential disease genes and interpret variants detected in patients. It also facilitates studies into why different mutations in the same gene can produce different symptoms and disease courses. The catalogue may also help reconstruct networks of relationships between receptors, their substrates, and other ligases, which is important for understanding why cells can sometimes compensate for the effects of a mutation, while in other cases disease develops', says Natalia Szulc, a doctoral candidate in the Laboratory of Protein Metabolism at IIMCB and the first author of the paper, quoted in a press release sent to PAP.

'In rare diseases, we often identify a variant in a particular gene without immediately understanding its biological consequences. Our work shows that when such a variant affects a substrate receptor, it can disrupt protein recognition, impair the ligase complex, or disturb other cellular processes important for the organism's development and function. This makes it easier to connect a genetic change with the disease mechanism and understand why it leads to particular symptoms', says co-author Professor Wojciech Pokrzywa, Head of the Laboratory of Protein Metabolism at IIMCB.

The researchers believe their work could be a starting point for further research and the development of new therapies.

'Targeted protein degradation is now an important direction in the development of new therapies. Rare diseases show how precisely the ubiquitin–proteasome system must operate: altering a single component can have serious consequences that emerge only in particular tissues or at specific stages of development', Pokrzywa says.

He adds that by analysing variants found in patients, we can better understand which features of substrate receptors determine the function of cullin–RING complexes, which substrate interactions might be amenable to modulation, and where the limitations of therapies based on targeted protein degradation may lie.

'This provides valuable guidance for designing safer and more precise therapeutic strategies', he says.

Joanna Morga (PAP)

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