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Structural predictions by AlphaFold uncover new protein functions

PNAS and Nature papers by Virus centre-affiliated researchers

With the advent of next generation sequencing, our understanding of the genetic diversity of cellular and viral life has expanded exponentially. Structural and mechanistic understanding of protein function has lagged behind due to the challenging and lowthroughput nature of structural and biochemical approaches. This situation changed dramatically by the development of AI structure prediction methods such as AlphaFold. Since protein structure is more conserved over evolutionary timescales than its amino acid sequence, reliable structure prediction by AlphaFold has revolutionised our ability to predict protein function.


In two recent bioinformatics-driven studies, Virus centre-affiliated researchers Gemma Atkinson and Vasili Hauryliuk took a closer look at the unexplored diversity of toxin-antitoxin (TA) systems (1,2). These ubiquitous microbial genetic elements are composed of a protein toxin inhibited by an antitoxin. While TAs have a variety of functions, one function that has recently stepped into the limelight recently is a role in defence against bacterial viruses, bacteriophages. Once the TA system detects the invading phage, the toxin is activated, compromising the viability of the infected bacterial cell. The infected cell commits altruistic suicide to protect the uninfected population. In 2022 the Hauryliuk-Atkinson team discovered and characterised the mechanism of antiviral defence by the CapRel TA system (3). Now, the researchers have predicted and validated numerous new TAs (1,2), advancing the field of bacterial antiviral immunity mechanisms.


Earlier this year, Gemma Atkinson established an AlphaFold facility at Lund University, LU-Fold LU-Fold specialises in high-throughput prediction of protein complexes to predict novel protein-protein interactions. Users do not have to have any previous bioinformatics or structural biology experience. Now the facility is up and running and Lund researchers are welcome to submit their requests.


1. Ernits K, Saha CK, Brodiazhenko T, Chouhan B, Shenoy A, Buttress JA, Duque-Pedraza JJ, Bojar V, Nakamoto JA, Kurata T, Egorov A, Shyrokova L, Johansson MJO, Mets T, Rustamova A, Dzigurski, Jelisaveta, Tenson T, Garcia-Pino A, Strahl H, Elofsson A, Hauryliuk V, Atkinson GC (2023) The structural basis of hyperpromiscuity in a core combinatorial network of Type II toxin-antitoxin and related phage defence systems. Proceedings of the National Academy of Sciences of the United States of America, 120(33):e2305393120


2. Durairaj J, Waterhouse A, Mets T, Brodiazhenko T, Abdullah M, Studer G, Akdel M, Andreeva A, Bateman A, Tenson T, Hauryliuk V, Schwede T, Pereira J (2023) Uncovering new families and folds in the natural protein universe. Nature, DOI: 10.1038/s41586-023-06622-3


3. Zhang T, Tamman H, Wallant KC, Kurata T, LeRoux M, Srikant S, Brodiazhenko T, Cepauskas A, Talavera A, Marteens C, Atkinson GC, Hauryliuk V, Garcia-Pino A, Laub MT (2022) Direct activation of an innate immune system in bacteria by a viral capsid protein. Nature, 612(7938):132-140


Uncovering new families and folds in the natural protein universe

The structural basis of hyperpromiscuity in a core combinatorial network of type II toxin–antitoxin and related phage defense systems