Discovery of Viral 'Sponge' Proteins
Genes in phages, viruses that infect bacteria, largely consist of "dark matter" – genes with unknown functions. Less than four years ago, a team led by Prof. Rotem Sorek at the Weizmann Institute of Science identified a new type of protein within this dark matter, named "sponge" proteins.
These porous proteins trap communication molecules essential for bacterial immune systems, allowing phages to control the bacterium and multiply.
Innovative Research Unveils New Sponge Families
Previously, few sponge proteins were identified due to their diverse genetic sequences. Researchers in Sorek's lab, utilizing artificial intelligence (AI) and experimental biology, have uncovered new families of sponge proteins that disrupt bacterial immune communication. The findings, published in Science, detail how viruses silence immune system signals and emphasize the role of communication disruption in the host-pathogen arms race.
AI-Powered Structural Pattern Recognition
Researchers observed a recurring architectural pattern in known sponge proteins: small structures composed of identical subunits with deep, positively charged pockets.
These pockets are designed to absorb negatively charged immune alarm molecules.
This insight allowed for the use of advanced AI tools, such as Google's AlphaFold, to scan a database of 32 million phage protein genes from 2 million phage genomes. AlphaFold predicted their three-dimensional structures, identifying over 120 candidate proteins that matched the structural criteria.
Experimental Validation and the Discovery of Novel Families
The identified candidates underwent experimental testing for effectiveness against five bacterial immune systems. This rigorous process led to the discovery of new sponge protein families:
- Lockin: This family was predicted by the AI model to consist of six identical subunits in a circular arrangement. This prediction was confirmed through X-ray crystallography, which also deciphered the mechanism of immune alarm molecule capture. Lockin proteins were found in hundreds of phages not previously isolated in labs.
- Sequestin: Identified by observing that genes encoding known sponge proteins tend to be fused together in phage genomes.
- Acb5: These proteins demonstrated the ability to not only trap but also cut alarm molecules, despite lacking typical structural features of molecular cutting tools. This discovery challenged previous assumptions.
Broad Implications for Antiviral Therapies
The protein families discovered in this study are present in the genomes of thousands of different phages in nature. A single phage can carry multiple types of sponges and enzymes to neutralize immune alarm molecules, indicating that disrupting immune communication provides a significant advantage in the competition between phages and bacteria.
The computational and experimental approach developed by the researchers enables testing for sponge proteins in viruses that infect plants, animals, and humans.
If found, sponge proteins could become targets for the development of future antiviral therapies.
The discovery method's independence from prior knowledge of protein function, sequence similarities, or laboratory isolation makes it a powerful tool for identifying additional immune-related proteins based on shared structural patterns.