Understanding protein evolutionary rate by integrating gene co-expression with protein interactions

Background: Among the many factors determining protein evolutionary rate, protein-protein interaction degree (PPID) has been intensively investigated in recent years, but its precise effect on protein evolutionary rate is still heavily debated.Results: We first confirmed that the correlation between protein evolutionary rate and PPID varies considerably across different protein interaction datasets. Specifically, because of the maximal inconsistency between yeast two-hybrid and other datasets, we reasoned that the difference in experimental methods contributes to our inability to clearly define how PPID affects protein evolutionary rate. To address this, we integrated protein interaction and gene co-expression data to derive a co-expressed protein-protein interaction degree (ePPID) measure, which reflects the number of partners with which a protein can permanently interact. Thus, irrespective of the experimental method employed, we found that (1) ePPID is a better predictor of protein evolutionary rate than PPID, (2) ePPID is a more robust predictor of protein evolutionary rate than PPID, and (3) the contribution of ePPID to protein evolutionary rate is statistically independent of expression level. Analysis of hub proteins in the Structural Interaction Network further supported ePPID as a better predictor of protein evolutionary rate than the number of distinct binding interfaces and clarified the slower evolution of co-expressed multi-interface hub proteins over that of other hub proteins.Conclusions: Our study firmly established ePPID as a robust predictor of protein evolutionary rate, irrespective of experimental method, and underscored the importance of permanent interactions in shaping the evolutionary outcome.