Журнал протеомики и биоинформатики
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New Minimotifs and their Functions in the C-Terminome

Surbhi Sharma1, Nemanja Novakovic1, Zachary Thomas FitzHugh1,2, Alexandria Bragg1, Stephen Brooks1, Xiaogang Wu2, Martin R. Schiller1,2*

Several protein domains and receptors recognize minimotifs on the short carboxyl termini of proteins and control protein clustering, trafficking, and posttranslational modifications. These functional C-terminal minimotifs are found on approximately 17% of proteins in the human proteome, with 83% of unknown functional significance. We tested a bioinformatic/proteomic approach to systematically identify new C-terminal minimotif functions. We selected 30 putative consensus C-terminal minimotifs based on their fold-enrichment and sequence complexity. These 30 consensus minimotifs had instances on 16% of the C-termini in the human proteome. Binding partners for a representative instance for each consensus C-terminal minimotif were identified by affinity purification liquid chromatography-tandem mass spectrometry. We validated the approach with a PDZ binding C-terminal minimotif instance, SDV> and identified 436 potential new interactors. For 7 of the 30 new C-terminal minimotifs, 32 previously known interactors were rediscovered. Overall, the experiments support 2,048 new binding partners to the 30 C-terminal minimotifs. Many interactors of the LxxxI> and QxxL> minimotif sequence patterns have role in RNA splicing and cell cycle, respectively. The key consensus residues for the new minimotifs were at positions of pathogenic mutations for 6 diseases giving insight into disease mechanism. In conclusion, the 30 new C-terminal consensus minimotifs cover 16% of the human C-terminome, help identify potential disease mechanisms, and this approach can be scaled to determine functions of protein C-termini in the human C-terminome.