Protein-protein interactions mediate a vast range of cellular functions, requiring diverse modes of binding. While recent years have seen major efforts to chart and classify the protein structure universe, we lack comparable methods to assess and cluster that diversity in interface structure at interactome scale. Here, we present Foldseek-Interface, a method that converts 3D interface structures into searchable sequences to enable fast alignment and clustering of protein interaction interfaces. It matches the accuracy of state-of-the-art tools while running up to 230 times faster. Applying it to all biological assemblies in the PDB, we cluster 3.1 million dimers into 77,167 interface clusters and use this resource to characterise interface diversity, evolution, and pathogen mimicry. Application of Foldseek-Interface to resources of predicted protein complex structures rapidly revealed putatively novel interface types worth further experimental interrogation. Foldseek-Interface and the interface cluster resource are freely available as webservers for search (https://search.foldseek.com/interface) and exploration (https://interface.foldseek.com).
J. M. Strom, Sooyoung Cha, R. Kim et al.· bioRxiv· 0 citations
Variant effect prediction remains a key challenge in precision medicine. Computational models are increasingly successful in the characterization of missense variants in folded protein regions. However, 37% of all annotated missense variants reside in the 25% of the proteome that is intrinsically disordered, lacking positional sequence conservation and stable structures. To advance the characterization of variants in intrinsically disordered protein regions (IDRs), we combined sequence pattern searches with AlphaFold to structurally annotate 1,300 protein–protein interactions with interfaces mediated by short disordered motifs binding to folded domains in partner proteins. These interfaces were selected based on their overlap with uncertain missense variants enabling structural model-based prediction of deleterious effects of 1,187 of these variants in IDRs. Extensive experimental efforts validated the predicted interfaces and deleterious variant effects that were predicted as benign by AlphaMissense, demonstrating that the combination of sequence analysis and structural modeling can readily generate numerous testable hypotheses of variant effects on protein function in IDRs. Proteome-wide prediction and structural modeling of disordered protein interaction interfaces advance characterization of disease-associated variants in disordered protein regions.
D. Hubrich, Jesús Alvarado Valverde, C. Y. Lee et al.· Nature Structural & Molecula...· 0 citations