Figure 3

(A) Negative selection of PTM regions is apparent in different modification types, in central residues modified by PTMs (left) and in flanking regions. (B) PTM regions often contain multiple types of modifications. (C) Negative selection is stronger in regions with clustered PTMs. (D) Variation analysis of kinase binding motifs reveals 24 kinases whose motif-breaker sites are negatively selected in the population (14 kinases), enriched in PTM-specific disease mutations (19 kinases) or both (9 kinases, shown in boldface). Motif-breaker sites are protein residues that disrupt kinase binding motifs when substituted. (E) Network of kinase-substrate interactions mediated by motif-breaker sites of the 24 kinases. Disease gene interactions are shown in red and black dots represent kinases with significant motif-breaker sites. Boxplot shows that disease genes have more interactions with motif-breaker sites than other proteins. (F) Protein residues highlighted as motif-breaker sites of the 24 kinases, shown relative to PTM site. Motif-breaker sites accumulate within 3 residues and are enriched in R,K,Q,E amino acids. Expected values from amino acid weighted permutations are shown with error bars indicating ±1 s.d.