Protein–Protein Interaction Hotspots Carved into Sequences

By Yanay Ofran, Burkhard Rost. 2007

258 citations recorded by the source corpus.

Protein–protein interactions, a key to almost any biological process, are mediated by molecular mechanisms that are not entirely clear. The study of these mechanisms often focuses on all residues at protein–protein interfaces. However, only a small subset of all interface residues is actually essential for recognition or binding. Commonly referred to as “hotspots,” these essential residues are defined as residues that impede protein–protein interactions if mutated. While no in silico tool identifies hotspots in unbound chains, numerous prediction methods were designed to identify all the residues in a protein that are likely to be a part of protein–protein interfaces. These methods typically identify successfully only a small fraction of all interface residues. Here, we analyzed the hypothesis that the two subsets correspond (i.e., that in silico methods may predict few residues because they preferentially predict hotspots). We demonstrate that this is indeed the case and that we can therefore predict directly from the sequence of a single protein which residues are interaction hotspots (without knowledge of the interaction partner). Our results suggested that most protein complexes are stabilized by similar basic principles. The ability to accurately and efficiently identify hotspots from sequence enables the annotation and analysis of protein–protein interaction hotspots in entire organisms and thus may benefit function prediction and drug development. The server for prediction is available at http://www.rostlab.org/services/isis.

Subfields: Molecular Biology

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Citations in the corpus

Predicting Protein Ligand Binding Sites by Combining Evolutionary Sequence Conservation and 3D Structure (2009, background): “including ligand binding sites [1–3], DNA-binding sites [4], catalytic sites [2,5], protein-protein interaction interfaces (PPIs) [6,7] and specificity determining positions [8–12].”
BeAtMuSiC: prediction of changes in protein–protein binding affinity on mutations (2013, methodology): “Although knowledge of the structure of the complex is generally required, methods have also been implemented to predict the localization of hotspots directly from the sequence (18), or from docking simulations (22).”
Disease-related mutations predicted to impact protein function (2012, methodology): “ISIS predicted binding hot spots stronger than other residues involved in the interaction [26].”