MOTIVATION: An important class of protein interactions involves the binding of a protein's domain to a short linear motif (SLiM) on its interacting partner. Extracting such motifs, either experimentally or computationally, is challenging because of their weak binding and high degree of degeneracy. Recent rapid increase of available protein structures provides an excellent opportunity to study SLiMs directly from their 3D structures. RESULTS: Using domain interface extraction (Diet), we characterized 452 distinct SLiMs from the Protein Data Bank (PDB), of which 155 are validated in varying degrees-40 have literature validation, 54 are supported by at least one domain-peptide structural instance, and another 61 have overrepresentation in high-throughput PPI data. We further observed that the lacklustre coverage of existing computational SLiM detection methods could be due to the common assumption that most SLiMs occur outside globular domain regions. 198 of 452 SLiM that we reported are actually found on domain-domain interface; some of them are implicated in autoimmune and neurodegenerative diseases. We suggest that these SLiMs would be useful for designing inhibitors against the pathogenic protein complexes underlying these diseases. Our findings show that 3D structure-based SLiM detection algorithms can provide a more complete coverage of SLiM-mediated protein interactions than current sequence-based approaches.

BACKGROUND: An important class of interaction switches for biological circuits and disease pathways are short binding motifs. However, the biological experiments to find these binding motifs are often laborious and expensive. With the availability of protein interaction data, novel binding motifs can be discovered computationally: by applying standard motif extracting algorithms on protein sequence sets each interacting with either a common protein or a protein group with similar properties. The underlying assumption is that proteins with common interacting partners will share some common binding motifs. Although novel binding motifs have been discovered with such approach, it is not applicable if a protein interacts with very few other proteins or when prior knowledge of protein group is not available or erroneous. Experimental noise in input interaction data can further deteriorate the dismal performance of such approaches. RESULTS: We propose a novel approach of finding correlated short sequence motifs from protein-protein interaction data to effectively circumvent the above-mentioned limitations. Correlated motifs are those motifs that consistently co-occur only in pairs of interacting protein sequences, and could possibly interact with each other directly or indirectly to mediate interactions. We adopted the (l, d)-motif model and formulate finding the correlated motifs as an (l, d)-motif pair finding problem. We present both an exact algorithm, D-MOTIF, as well as its approximation algorithm, D-STAR to solve this problem. Evaluation on extensive simulated data showed that our approach not only eliminated the need for any prior protein grouping, but is also more robust in extracting motifs from noisy interaction data. Application on two biological datasets (SH3 interaction network and TGFbeta signaling network) demonstrates that the approach can extract correlated motifs that correspond to actual interacting subsequences. CONCLUSION: The correlated motif approach outlined in this paper is able to find correlated linear motifs from sparse and noisy interaction data. This, in turn, will expedite the discovery of novel linear binding motifs, and facilitate the studies of biological pathways mediated by them.