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Fig. 1 | Cell Communication and Signaling

Fig. 1

From: Short linear motifs – ex nihilo evolution of protein regulation

Fig. 1

Conservation of functionally important motifs and the proliferation of motifs through ex nihilo motif acquisition. a Alignment of the PCNA-binding PIP box motif of Flap endonuclease 1 (FEN1) showing the motif conservation spanning over 3 billion years of evolution across all Eukaryotes and Archaea (representative species - Thermococcus kodakaraensis) [24, 25, 108]. b An alignment of a representative selection of PxIxIT motif instances: Nuclear factor of activated T-cells, cytoplasmic 1 (NFATC1) [109], A-kinase anchor protein 5 (AKAP5) [110] and Potassium channel subfamily K member 18 (KCNK18) [111] from human; Phosphatidylinositol 4,5-bisphosphate-binding protein SLM1 (Slm1) [112], Protein HPH1 (Hph1) [113] and Transcriptional regulator CRZ1 (Crz1) from yeast [114]; and Ankyrin repeat domain-containing protein A238L from African swine fever virus (ASFV) [115]. Each motif instance occurs in a non-homologous protein (see panel c) and the most likely mode of acquisition for these functional modules is by ex nihilo evolution through random mutation. The alignment shows a clear preference for specific residues at a given position in the peptide with each position allowing a different level of degeneracy. These preferences reflect the preferences of the Calcineurin PxIxIT binding pocket (see panel d). c The modular architecture of the proteins from panel B showing the distinct organisation of the non-homologous proteins. Domains (grey), transmembrane regions (green) and PxIxITs (blue) are shown. Proteins are aligned around the PxIxIT instances. d Structure of the PxIxIT binding pocket of the human calcineurin catalytic A subunit bound to the PxIxIT of African swine fever virus A238L (PDB ID:4F0Z) [115]. The peptide binds by beta-augmentation and the defined residues at P1, P3, P5 sit in a conserved hydrophobic pocket explaining the strong preferences at these positions in known PxIxIT instances (light blue surface on the domain denotes hydrophobic residues) [109, 110, 116]

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