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Table 1 Table of characterised examples of motif gain and loss modulating protein function

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

Species protein (Gene) Motif Sequencea Evolution Function
Ex nihilo motif acquisition
H. sapiens Leucine-rich repeat protein SHOC-2 (SHOC2) N-myristoylation motif 1 MGSSLG 6 Allele with a single S2- > G mutation in SHOC2 in Noonan-like syndrome patients “knocks in” a motif [26]. N-myristoylation of SHOC2
H. sapiens Adapter molecule crk (CRK) ABL1 SH3 domain binding motif 69PPVPPSPAQP78 Ex nihilo acquisition in early mammals [85]. Recruitment of ABL1 to CRK
S.cerevisiae Cell division control protein 6 (Cdc6) SCF Cdc4 degrons 364QVPLTPTTSPVK375 Ex nihilo acquisition in Saccharomyces sensu stricto clade [57]. Degradation of Cdc6 by the SCF E3 Ub ligase
M. musculus E3 ubiquitin-protein ligase Mdm2 (Mdm2) Cyclin binding motif 179KKRRRSLSFDPS189 Acquisition in the rodent lineage via a four amino acid deletion [117]. Recruitment of and phosphorylation by CDK2
D. melanogaster Segmentation polarity homeobox protein engrailed (en) Groucho interacting motif 198QASIFRPFEAS208 Ex nihilo acquisition in diptera/lepidoptera [134]. Recruitment of groucho
S.cerevisiae Serine/threonine-protein kinase ELM1 (Elm1) Calcineurin docking motif 465KVTPSIHIDEEP476 Ex nihilo acquisition in Saccharomyces sensu stricto clade [27]. Recruitment of and dephosphorylation by calcineurin
Influenza hemagglutinin (H3) N-glycosylation motifs Five NxT sites Strains spanning the last 40 years have shown gradual acquisition of five novel N-glycosylation sites [118]. Increased immune system evasion and decreased infectivity
Motif gain/loss post duplication
S. cerevisiae Spindle assembly checkpoint component MAD3 (Mad3) APC/C Cdc20 binding KEN box 27ETQKENILP35 Lost in the Bub1 functional homologues after Mad3-like/Bub1-like duplications [41]. Loss of APC/C inhibitory function
S. cerevisiae Metallothionein expression activator (Ace2) Cbk1 docking motif 280NGGYQFPPPTL291 Lost in Swi5 after Swi5/Ace2 duplication [36]. Loss of Cbk1 regulated localisation
H. sapiens Cyclin-A2 (CCNA2) APC/C CDC20 binding ABBA motif 96QPAFTIHVDEAE108 Ex nihilo acquisition in Cyclin A after the Cyclin A/Cyclin B duplication [40]. Early degradation during an active spindle assembly checkpoint
Tuning of motif specificity/affinity
S. cerevisiae MAP kinase kinase Pbs2 (Pbs2) Sho1 SH3 domain binding motif 90IVNKPLPPLPVAG102 Only binds the SH3 domain of yeast Sho1 but can be recognised by multiple non-yeast SH3 domains [53]. Specific interaction with Sho1
S. cerevisiae Peroxisomal membrane protein PEX14 (Pex14) Pex14 SH3 domain binding motif 84AMPPTLPHRD93 Promiscuous in vitro but only binds the SH3 domain of co-localised Pex13 in vivo [53]. Promiscuous in vitro interactions
Ex nihilo co-operative/competitive interface evolution
S. cerevisiae N-acetyltransferase ECO1 (Eco1) SCF Cdc4 degron 90TGTITPLNSSPL101 Ex nihilo acquisition in the Saccharomycetaceae clade of four motifs required for sequential kinase and ubiquitin ligase recruitment [58]. Degradation of Eco1 by the SCF E3 Ub ligase
Mck1 modification site 91GTITPLNSSPL101
Cdc7 modification site 95PLNSSPLKK103
Cdk1 modification site 96LNSSPLKKSS105
S. cerevisiae DNA replication licensing factor MCM3 (Mcm3) Cdk1 modification sites 758SKRSPQKSPK767 Ex nihilo acquisition of a cluster of Cdk1 modification sites in the Saccharomycetaceae family [54]. Regulation of nucleocytoplasmic shuttling of Mcm3
S. cerevisiae DIG2 (Dig2) MAPK D-site 97HSLKRKRVPPALNFSDI113 Acquisition of MAPK D-site followed by ex nihilo acquisition of overlapping calcineurin-binding PxIxIT site; Dig1 paralog contains D-site but no PxIxIT [27, 135]. Competitive recognition of substrate by kinase and phosphatase
  Calcineurin PxIxIT 103RVPPALNFSIQA114
H. sapiens Retinoblastoma-associated protein RB (RB1) Cyclin A docking site 873 KKLRF 875 Co-evolution of PP1 and Cyclin A recognition motifs [56, 136]. Competitive recognition of substrate by kinase and phosphatase
PP1 binding RVxF 873KKLRF 877
Motif gain/loss post de novo gene birth
 Human immunodeficiency virus type 1 (HIV-1) Protein Vpu (vpu) SCF β-TrCP degron 48RAEDSGNESEGE59 Ex nihilo acquisition in the novel overprinted Vpu protein, present only HIV-1 and its simian precursors [44, 45]. Highjacking of the host SCF-β-TrCP E3 Ub ligase
  1. aSequence overlapping motif - the major specificity and affinity determining residues of the motif are underlined and in bold