Mining proteomes for short motifs(possible potential as bioactive peptides)

• Proteomes – Man– pathogens – food organisms

• Computation– Evolutionary conservation– Evolutionary convergence– Predicting SLiM-like properties

Short linear motifs SLiMPRED predictor

α-Helix β-Sheet Polyproline II

LIG_EH1_1 LIG_Dynein_DLC8_1 LIG_CAP-Gly_1LIG_GLEBS_BUB3_1 LIG_PDZ_1 LIG_SH3_1

LIG_IQ LIG_PP1 LIG_SH3_2

LIG_MDM2 LIG_PP2B_1 LIG_SH3_3

LIG_NRBOX LIG_SH2_GRB2 LIG_SH3_5

LIG_Sin3_1 LIG_SH2_SRC LIG_TRAF2_1

LIG_Sin3_3 LIG_SH2_STAT3 LIG_TRAF6

LIG_SH2_STAT5 LIG_WW_1

LIG_SIAH_1

LIG_TRFH_1

LIG_WRPW_1

Restricted training set to protein-binding motifs including:

Training a short linear motif predictor (SLiMPred)

α-Helix β-Sheet Polyproline II Othersequences 30 49 30 141Unique ELMs 7 11 8 31SLiM residues 387 324 218 1239197,410 Non-SLiM residues

Most motifs lie in disordered regions of proteinsExisting predictor ANCHOR predicts protein-binding within disordered regions

SLiMPred (blue) v ANCHOR (red)

Alpha-helix Beta-sheet

Polyproline-II helixOther

SLIMPred has some predictive ability in ordered regions too

Disordered regions

Ordered regions

SLiMPred: predicting motif-like regions along a protein

DisorderSLIMPredRelative LocalConservation

http://bioware.ucd.ie Mooney et al J Mol Biol (2012) 415:193-204

Which kinds of interactions should we use in searching for novel motifs?

ALL Yeast 2 hybrid

complex

• http://bioinfo-casl.ucd.ie/empa/programberlin/2-uncategorised/52

Potential workflows to identify novel peptides from proteins

• Conservation analysis• SLiMPrints

• Convergent evolution analysis • SLiMFinder

• Extracellular peptides • PeptideRanker

• Intracellular peptides• SLiMPred• ANCHOR

• Known structure of protein ligand, candidate peptide sequence• Pepsite (Trabuco et al Nucleic Acids Res. 2012)

• Known structure with linear peptide in complex• Predict cyclised peptide mimetic (CYCLOPS virtual library; Duffy et al 2012).

SLiMFinder human known versus the newKnown true positive motifs are discovered With variations in many protein interaction sets

Novel motifs are much sparser, often only discovered once

• All the human motif discovery results are available in an online searchable database (search on genes or motifs) bioware.soton.ac.uk/slimdb