Towards a structurally resolved human protein interaction network
By D. Burke, Patrick Bryant, Inigo Barrio‐Hernandez, Danish Memon, Gabriele Pozzati, Aditi Shenoy, Wensi Zhu, Alistair S. Dunham, P. Albanese, Andrew Keller and 6 more. 2021
210 citations recorded by the source corpus.
Here the authors explore the ability of AlphaFold2 to predict structures across the human protein-protein interactome and the limitations thereof. Cellular functions are governed by molecular machines that assemble through protein-protein interactions. Their atomic details are critical to studying their molecular mechanisms. However, fewer than 5% of hundreds of thousands of human protein interactions have been structurally characterized. Here we test the potential and limitations of recent progress in deep-learning methods using AlphaFold2 to predict structures for 65,484 human protein interactions. We show that experiments can orthogonally confirm higher-confidence models. We identify 3,137 high-confidence models, of which 1,371 have no homology to a known structure. We identify interface residues harboring disease mutations, suggesting potential mechanisms for pathogenic variants. Groups of interface phosphorylation sites show patterns of co-regulation across conditions, suggestive of coordinated tuning of multiple protein interactions as signaling responses. Finally, we provide examples of how the predicted binary complexes can be used to build larger assemblies helping to expand our understanding of human cell biology.
Subfields: Computational Theory and Mathematics, Molecular Biology
How researchers see this paper
The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.
In Computational Theory and Mathematics
- Carlos H. M. Rodrigues
- Douglas E. V. Pires
- David B. Ascher
- Sergey Ovchinnikov
- Alfonso Valencia
- Gabriele Pozzati
- Arne Elofsson
- T. Croll
In Molecular Biology
- Arne Elofsson
- Sergey Ovchinnikov
- Yang Zhang
- Carlos H. M. Rodrigues
- Douglas E. V. Pires
- David B. Ascher
- Gabriele Pozzati
- Janet M. Thornton
Citations in the corpus
- A structural biology community assessment of AlphaFold2 applications (2021, methodology): “We have expanded on this analysis in a companion manuscript 20 and have used this approach to predict complexes of human protein interactions on a large scale 56 .”
- Clustering predicted structures at the scale of the known protein universe (2023, background): “AlphaFold2 and its predicted structures have now been used for diverse applications, including studies of protein pockets 6 , prediction of structures of complexes 7,8 , studies of structural similarity 9 , novel fold predictions 10 and even improvement of genomic annotation 11 .”