Protein-protein interactions and disease: use of S. cerevisiae as a model system

Disease-causing mutations are increasingly being studied to see if they cause the loss or gain of protein-protein interactions. Because the interaction network of humans is poorly understood and difficult to investigate, here we propose the use of Saccharomyces cerevisiae as a model system for understanding the impact of disease-causing mutations on protein-protein interactions. Alignments of human disease-associated proteins and 379 yeast orthologs showed that 124 of these proteins have >40% sequence identity, with some orthologs having up to 89% identity. A total of 1826 amino acid mutations associated with human disease were found to map to invariant amino acids in yeast. These mutations were proportionately more likely to be non-conservative than non-disease associated polymorphisms for the same proteins (p=0.016). Importantly, 73 of the mutations mapped to protein-protein interaction domains, implying a direct link between mutation and changes in protein interactivity. In the manuscript, all alignment information and tables that map mutations and diseases to yeast orthologs are given. This will help researchers experimentally test the impact of mutations on protein-protein interactions in S. cerevisiae and, by homology, explore the role of such mutations in the genesis of human disease.