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 |
762PQKSPKKRQR771 | ||||
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 |