Protein-protein interaction hotspots carved into sequences

Yanay Ofran, Burkhard Rost

Research output: Contribution to journalArticlepeer-review

225 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1169-1176
Number of pages8
JournalPLoS Computational Biology
Volume3
Issue number7
DOIs
StatePublished - Jul 2007
Externally publishedYes

Funding

FundersFunder number
National Institute of General Medical SciencesR01GM064633
U.S. National Library of MedicineR01LM007329

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