Fig. 4
From: Short linear motifs – ex nihilo evolution of protein regulation
Examples of motif-binding pocket evolution. a Representative selection of motif-binding pockets in the WD40 repeat fold demonstrating the simplicity of motif-binding pocket birth. Each pocket has evolved independently and subsequently multiple proteins (representative examples listed) have acquired the motifs necessary to recruit the various WD40 repeat containing proteins. The figure includes: an ABBA motif (dark blue – consensus [ILV][FHY]x[DE]), a D box degron motif (red – consensus RxxLxx[ILVK]) and a KEN box degron motif (yellow – consensus KEN) from APC/C-CDH1 modulator 1 (Acm1) bound to the WD40 domain of the APC/C activator protein CDH1 (Cdh1) [69]; an Fbw7 degron motif (orange – consensus pTPxxpS) from Cyclin E bound to the WD40 domain of the F-box/WD repeat-containing protein 7 (FBW7) [123]; a β-TrCP1 degron motif (light blue – consensus DpSGxxpS) from β-Catenin bound to the WD40 domain of the F-box/WD repeat-containing protein 1A (BTRC) [131]; and an EH1 motif (green – consensus [FHY]x[IVM]xx[ILM][ILMV]) bound to the WD40 domain of the Transducin-like enhancer protein 1 (TLE) [132]. See the ELM resource for more details and examples [9]. b Example of specificity divergence after motif–binding domain duplication. A homologous pocket on the protein phosphatase 1 (PP1) and calcineurin holoenzymes bind RVxF and PxIxIT motifs respectively. The structure shows the canonical PP1 binding sequence RVxF motif (light blue) of myosin phosphatase targeting subunit (MYPT1) bound to PP1 (grey). The PxIxIT of African swine fever virus A238L (A238L) (orange) is superimposed showing the shared but diverged binding pocket [115]. The valine and phenylalanine of the RVxF motif sit in the hydrophobic P1 and P3 regions occupied by the proline and first isoleucine of the PxIxIT binding pocket (see Fig. 1d) but the additional specificity/affinity determinants of the two motifs utilise different surfaces of the domain and do not overlap [50, 133]