Systematic Prediction of Scaffold Proteins Reveals New Design Principles in Scaffold-Mediated Signal Transduction

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Abstract
Scaffold proteins play a crucial role in facilitating signal transduction in eukaryotes by bringing together multiple signaling components. In this study, we performed a systematic analysis of scaffold proteins in signal transduction by integrating protein-protein interaction and kinase-substrate relationship networks. We predicted 212 scaffold proteins that are involved in 605 distinct signaling pathways. The computational prediction was validated using a protein microarray-based approach. The predicted scaffold proteins showed several interesting characteristics, as we expected from the functionality of scaffold proteins. We found that the scaffold proteins are likely to interact with each other, which is consistent with previous finding that scaffold proteins tend to form homodimers and heterodimers. Interestingly, a single scaffold protein can be involved in multiple signaling pathways by interacting with other scaffold protein partners. Furthermore, we propose two possible regulatory mechanisms by which the activity of scaffold proteins is coordinated with their associated pathways through phosphorylation process. Despite their importance in the signaling transduction, there is no systematic effort in identifying and characterizing the scaffold proteins in humans. In this work, we predicted scaffold proteins by integrating the available protein-protein interactions and kinase-substrate relationships. The predicted scaffold proteins showed characteristics for known scaffold proteins, suggesting the fidelity of our prediction. More importantly, the systematic prediction of scaffold proteins provides biological insights in the scaffold-mediated signal transduction. We found that scaffold proteins are likely to form complexes, suggesting that scaffold proteins could participate in diverse signaling pathways through the combinatorial interactions among scaffold proteins. Furthermore, the regulation of scaffold proteins’ activities has not been extensively studied. Our bioinformatics analysis proposed that scaffold proteins themselves might be regulated through phosphorylation process.

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