short linear motif

SLiMs are generally situated in intrinsically disordered regions {{cite journal | vauthors = Ren S, Uversky VN, Chen Z, Dunker AK, Obradovic Z | title = Short Linear Motifs recognized by SH2, SH3 and Ser/Thr Kinase domains are conserved in disordered protein regions | journal = BMC Genomics | volume = 9 | pages = S26 | date = September 2008 | issue = Suppl 2 | pmid = 18831792 | pmc = 2559891 | doi = 10.1186/1471-2164-9-S2-S26 | doi-access = free }} (over 80% of known SLiMs), however, upon interaction with a structured partner secondary structure is often induced. The majority of annotated SLiMs consist of 3 to 11 contiguous amino acids, with an average of just over 6 residues. However, only few hotspot residues (on average 1 hotspot for each 3 residues in the motif) contribute the majority of the free energy of binding and determine most of the affinity and specificity of the interaction. Although most motifs have no positional preference, several of them are required to be localized at the protein termini in order to be functional.{{cite journal | vauthors = London N, Movshovitz-Attias D, Schueler-Furman O | title = The structural basis of peptide-protein binding strategies | journal = Structure | volume = 18 | issue = 2 | pages = 188–99 | date = February 2010 | pmid = 20159464 | doi = 10.1016/j.str.2009.11.012 | doi-access = free }}{{cite journal | vauthors = Davey NE, Van Roey K, Weatheritt RJ, Toedt G, Uyar B, Altenberg B, Budd A, Diella F, Dinkel H, Gibson TJ | display-authors = 6 | title = Attributes of short linear motifs | journal = Molecular BioSystems | volume = 8 | issue = 1 | pages = 268–81 | date = January 2012 | pmid = 21909575 | doi = 10.1039/c1mb05231d | author-link10 = Toby Gibson }}

The key defining attribute of SLiMs, having a limited number of residues that directly contact the binding partner, has two major consequences. First, only few or even a single mutation can result in the generation of a functional motif, with further mutations of flanking residues allowing tuning affinity and specificity.{{cite journal | vauthors = Davey NE, Cyert MS, Moses AM | title = Short linear motifs - ex nihilo evolution of protein regulation | journal = Cell Communication and Signaling | volume = 13 | issue = 1 | pages = 43 | date = November 2015 | pmid = 26589632 | pmc = 4654906 | doi = 10.1186/s12964-015-0120-z | doi-access = free }} This results in SLiMs having an increased propensity to evolve convergently, which facilitates their proliferation, as is evidenced by their conservation and increased incidence in higher Eukaryotes.{{cite journal | vauthors = Ren S, Yang G, He Y, Wang Y, Li Y, Chen Z | title = The conservation pattern of short linear motifs is highly correlated with the function of interacting protein domains | journal = BMC Genomics | volume = 9 | pages = 452 | date = October 2008 | pmid = 18828911 | pmc = 2576256 | doi = 10.1186/1471-2164-9-452 | doi-access = free }} It has been hypothesized that this might increase and restructure the connectivity of the interactome. Second, SLiMs have relatively low affinity for their interaction partners (generally between 1 and 150 μM), which makes these interactions transient and reversible, and thus ideal to mediate dynamic processes such as cell signaling. In addition, this means that these interactions can be easily modulated by post-translational modifications that change the structural and physicochemical properties of the motif. Also, regions of high functional density can mediate molecular switching by means of overlapping motifs (e.g. the C-terminal tails of integrin beta subunits), or they can allow high avidity interactions by multiple low affinity motifs (e.g. multiple [http://elm.eu.org/elms/elmPages/LIG_AP2alpha_2.html AP2-binding motifs] in [https://www.uniprot.org/uniprot/P42566 Eps15]).{{cite journal | vauthors = Neduva V, Russell RB | title = Linear motifs: evolutionary interaction switches | journal = FEBS Letters | volume = 579 | issue = 15 | pages = 3342–5 | date = June 2005 | pmid = 15943979 | doi = 10.1016/j.febslet.2005.04.005 | s2cid = 41014984 | doi-access = free | bibcode = 2005FEBSL.579.3342N }}{{cite journal | vauthors = Gibson TJ | title = Cell regulation: determined to signal discrete cooperation | journal = Trends in Biochemical Sciences | volume = 34 | issue = 10 | pages = 471–82 | date = October 2009 | pmid = 19744855 | doi = 10.1016/j.tibs.2009.06.007 | author-link1 = Toby Gibson }}

SLiM functions in almost every pathway due to their critical role in regulatory function, protein-protein interaction and signal transduction. SLiM act as interaction modules that are recognised by additional biomolecules. The majority of known interaction partners of SLiMs are globular protein domains, though, SLiMs that recognise other intrinsically disordered regions, RNA and lipids have also been characterised. SLiMs can be broadly split into two high level classes, modification sites and ligand binding sites.

Modification sites
Modification sites SLiMs encompass sites with intrinsic specificity determinant that are recognised and modified by the active site of a catalytic domain of an enzyme. These SLiMs include many classical post translational modification sites (PTMs), proteolytic cleavage sites recognised by proteases and bonds recognised by isomerases.

• Moiety addition – SLiMs are often targeted for the addition of a small chemical groups (e.g. Phosphorylation), proteins (e.g. SUMOylation) or other moieties (e.g. post translational moiety addition).
• Proteolytic cleavage -SLiMs can act as recognition sites of endo-peptidases resulting in the irreversible cleavage of the peptide at the SLiM.
• Structural modifications – SLiMs can be recognised by isomerases resulting in the cis-trans isomerisation of the peptide backbone.

Ligand binding sites
Ligand binding site SLiMs recruit binding partners to the SLiM containing proteins, often mediating transient interactions, or acting co-operatively to produce more stable complexes. Ligand SLiMs are often central to the formation of dynamic multi-protein complexes, however, they more commonly mediate regulatory interactions that control the stability, localisation or modification state of a protein.{{Cite journal |last1=Cermakova |first1=Katerina |last2=Hodges |first2=H. Courtney |date=2023-02-06 |title=Interaction modules that impart specificity to disordered protein |journal=Trends in Biochemical Sciences |volume=48 |issue=5 |pages=S0968–0004(23)00008–7 |doi=10.1016/j.tibs.2023.01.004 |issn=0968-0004 |pmid=36754681|pmc=10106370 |doi-access=free }}

• Complex formation – Ligand SLiMs often function as simple interfaces that recruit proteins to multi-protein complexes (e.g. the Retinoblastoma-binding LxCxE motif) or act as aggregators in scaffold proteins (e.g. SH3 domain-binding proline-rich sequences).
• Localisation – A large number of SLiMs act as zipcodes that are recognized by the cellular transport machinery mediating the relocalisation of the containing protein to the correct sub-cellular compartment (e.g. Nuclear localisation signals (NLSs) and Nuclear export signals (NESs))
• Modification state – Many classes of ligand SLiMs recruit enzymes to their substrate by binding to sites that are distinct from the enzyme's active site. These site, known as docking motifs, act as additional specificity determinants for these enzymes and decrease the likelihood of off-target modification events.
• Stability – A subset of docking motifs recruit E3 ubiquitin ligase to their substrates. The resulting polyubiquitination targets the substrate for proteosomal destruction.

Disordered protein elements like SLiMs are frequently found in factors that regulate gene expression. As a result, several diseases have been linked to mutations that alter key SLiM-mediated functions. For instance, one cause of Noonan Syndrome is a mutation in the protein Raf-1 which abrogates the interaction with 14-3-3 proteins mediated by corresponding short linear motifs and thereby deregulate the Raf-1 kinase activity.{{cite journal | vauthors = Pandit B, Sarkozy A, Pennacchio LA, Carta C, Oishi K, Martinelli S, Pogna EA, Schackwitz W, Ustaszewska A, Landstrom A, Bos JM, Ommen SR, Esposito G, Lepri F, Faul C, Mundel P, López Siguero JP, Tenconi R, Selicorni A, Rossi C, Mazzanti L, Torrente I, Marino B, Digilio MC, Zampino G, Ackerman MJ, Dallapiccola B, Tartaglia M, Gelb BD | display-authors = 6 | title = Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy | journal = Nature Genetics | volume = 39 | issue = 8 | pages = 1007–12 | date = August 2007 | pmid = 17603483 | doi = 10.1038/ng2073 | s2cid = 19335210 }} Usher's Syndrome is the most frequent cause of hereditary deaf-blindness in humans{{cite journal | vauthors = Eudy JD, Sumegi J | title = Molecular genetics of Usher syndrome | journal = Cellular and Molecular Life Sciences | volume = 56 | issue = 3–4 | pages = 258–67 | date = October 1999 | pmid = 11212353 | doi = 10.1007/s000180050427 | pmc = 11146852 | s2cid = 2028106 }} and can be caused by mutations in either PDZ domains in Harmonin or the corresponding PDZ interaction motifs in the SANS protein.{{cite journal | vauthors = Kalay E, de Brouwer AP, Caylan R, Nabuurs SB, Wollnik B, Karaguzel A, Heister JG, Erdol H, Cremers FP, Cremers CW, Brunner HG, Kremer H | display-authors = 6 | title = A novel D458V mutation in the SANS PDZ binding motif causes atypical Usher syndrome | journal = Journal of Molecular Medicine | volume = 83 | issue = 12 | pages = 1025–32 | date = December 2005 | pmid = 16283141 | doi = 10.1007/s00109-005-0719-4 | s2cid = 41415771 }} Finally, Liddle's Syndrome has been implicated with autosomal dominant activating mutations in the WW interaction motif in the β-(SCNNB_HUMA) and γ-(SCNNG_HUMA) subunits of the Epithelial sodium channel ENaC.{{cite journal | vauthors = Warnock DG | title = Liddle syndrome: an autosomal dominant form of human hypertension | journal = Kidney International | volume = 53 | issue = 1 | pages = 18–24 | date = January 1998 | pmid = 9452995 | doi = 10.1046/j.1523-1755.1998.00728.x | doi-access = free }} These mutations abrogate the binding to the ubiquitin ligase NEDD4, thereby inhibiting channel degradation and prolonging the half-life of ENaC, ultimately resulting in increased Na⁺ reabsorption, plasma volume extension and hypertension.{{cite journal | vauthors = Furuhashi M, Kitamura K, Adachi M, Miyoshi T, Wakida N, Ura N, Shikano Y, Shinshi Y, Sakamoto K, Hayashi M, Satoh N, Nishitani T, Tomita K, Shimamoto K | display-authors = 6 | title = Liddle's syndrome caused by a novel mutation in the proline-rich PY motif of the epithelial sodium channel beta-subunit | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 90 | issue = 1 | pages = 340–4 | date = January 2005 | pmid = 15483078 | doi = 10.1210/jc.2004-1027 | doi-access = free }}

Viruses often mimic human SLiMs to hijack and disrupt a host's cellular machinery,{{cite journal | vauthors = Davey NE, Travé G, Gibson TJ | title = How viruses hijack cell regulation | journal = Trends in Biochemical Sciences | volume = 36 | issue = 3 | pages = 159–69 | date = March 2011 | pmid = 21146412 | doi = 10.1016/j.tibs.2010.10.002 }}{{cite journal | vauthors = Kadaveru K, Vyas J, Schiller MR | title = Viral infection and human disease--insights from minimotifs | journal = Frontiers in Bioscience | volume = 13 | issue = 13 | pages = 6455–71 | date = May 2008 | pmid = 18508672 | pmc = 2628544 | doi = 10.2741/3166 }} thereby adding functionality to their compact genomes without necessitating new virally encoded proteins. In fact, many motifs were originally discovered in viruses, such as the Retinoblastoma binding LxCxE motif and the UEV domain binding PTAP late domain. The short generation times and high mutation rates of viruses, in association with natural selection, has led to multiple examples of mimicry of host SLiMs in every step of the viral life cycle (Src binding motif PxxP in Nef modulates replication, WW domain binding PPxY mediates budding in Ebola virus, A Dynein Light Chain binding motif in Rabies virus is vital for host infection). The YGL motif (Tyrosine-Glycine-Leucine) is an integrin-binding motif present in several viral glycoproteins including Equine Herpes Virus (EHV) 1, EHV-4, and in rotavirus VP4.{{Cite journal|last1=Spiesschaert|first1=Bart|last2=Osterrieder|first2=Nikolaus|last3=Azab|first3=Walid|date=2015-02-03|title=Comparative Analysis of Glycoprotein B (gB) of Equine Herpesvirus Type 1 and Type 4 (EHV-1 and EHV-4) in Cellular Tropism and Cell-to-Cell Transmission|journal=Viruses|volume=7|issue=2|pages=522–542|doi=10.3390/v7020522|issn=1999-4915|pmc=4353902|pmid=25654240|doi-access=free}} The extent of human SLiM mimicry is surprising with many viral proteins containing several functional SLiMs, for example, the Adenovirus protein E1A.

Pathogenic bacteria also mimic host motifs (as well as having their own motifs), however, not to the same extent as the obligate parasite viruses. E. Coli injects a protein, EspF(U), that mimics an autoinhibitory element of N-WASP into the host cell to activate actin-nucleating factors WASP.{{cite journal | vauthors = Sallee NA, Rivera GM, Dueber JE, Vasilescu D, Mullins RD, Mayer BJ, Lim WA | title = The pathogen protein EspF(U) hijacks actin polymerization using mimicry and multivalency | journal = Nature | volume = 454 | issue = 7207 | pages = 1005–8 | date = August 2008 | pmid = 18650806 | pmc = 2749708 | doi = 10.1038/nature07170 | bibcode = 2008Natur.454.1005S }} The KDEL motif of the bacteria encoded cholera toxin mediates cell entry of the cholera toxin.{{cite journal | vauthors = Lencer WI, Constable C, Moe S, Jobling MG, Webb HM, Ruston S, Madara JL, Hirst TR, Holmes RK | display-authors = 6 | title = Targeting of cholera toxin and Escherichia coli heat labile toxin in polarized epithelia: role of COOH-terminal KDEL | journal = The Journal of Cell Biology | volume = 131 | issue = 4 | pages = 951–62 | date = November 1995 | pmid = 7490296 | pmc = 2200010 | doi = 10.1083/jcb.131.4.951 }}

File:Nutlin bound to MDM2.png

Linear motif mediated protein-protein interactions have shown promise in recent years as novel drug targets.{{cite journal | vauthors = Wells JA, McClendon CL | title = Reaching for high-hanging fruit in drug discovery at protein-protein interfaces | journal = Nature | volume = 450 | issue = 7172 | pages = 1001–9 | date = December 2007 | pmid = 18075579 | doi = 10.1038/nature06526 | bibcode = 2007Natur.450.1001W | s2cid = 205211934 }} Success stories include the MDM2 motif analog Nutlin-3 and integrin targeting RGD-mimetic Cilengitide: Nutlin-3 antagonises the interaction of MDM2's SWIB domain with p53 thus stabilising p53 and inducing senescence in cancer cells.{{cite journal | vauthors = Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C, Fotouhi N, Liu EA | display-authors = 6 | title = In vivo activation of the p53 pathway by small-molecule antagonists of MDM2 | journal = Science | volume = 303 | issue = 5659 | pages = 844–8 | date = February 2004 | pmid = 14704432 | doi = 10.1126/science.1092472 | bibcode = 2004Sci...303..844V | s2cid = 16132757 }} Cilengitide inhibits integrin-dependent signaling, causing the disassembly of cytoskeleton, cellular detachment and the induction of apoptosis in endothelial and glioma cells.{{cite journal | vauthors = Goodman SL, Hölzemann G, Sulyok GA, Kessler H | title = Nanomolar small molecule inhibitors for alphav(beta)6, alphav(beta)5, and alphav(beta)3 integrins | journal = Journal of Medicinal Chemistry | volume = 45 | issue = 5 | pages = 1045–51 | date = February 2002 | pmid = 11855984 | doi = 10.1021/jm0102598 }}{{cite journal | vauthors = Oliveira-Ferrer L, Hauschild J, Fiedler W, Bokemeyer C, Nippgen J, Celik I, Schuch G | title = Cilengitide induces cellular detachment and apoptosis in endothelial and glioma cells mediated by inhibition of FAK/src/AKT pathway | journal = Journal of Experimental & Clinical Cancer Research | volume = 27 | issue = 1 | pages = 86 | date = December 2008 | pmid = 19114005 | pmc = 2648308 | doi = 10.1186/1756-9966-27-86 | doi-access = free }} In addition, peptides targeting the Grb2 and Crk SH2/ SH3 adaptor domains are also under investigation.{{cite journal | vauthors = Gril B, Vidal M, Assayag F, Poupon MF, Liu WQ, Garbay C | title = Grb2-SH3 ligand inhibits the growth of HER2+ cancer cells and has antitumor effects in human cancer xenografts alone and in combination with docetaxel | journal = International Journal of Cancer | volume = 121 | issue = 2 | pages = 407–15 | date = July 2007 | pmid = 17372910 | pmc = 2755772 | doi = 10.1002/ijc.22674 }}{{cite journal | vauthors = Feller SM, Lewitzky M | title = Potential disease targets for drugs that disrupt protein-- protein interactions of Grb2 and Crk family adaptors | journal = Current Pharmaceutical Design | volume = 12 | issue = 5 | pages = 529–48 | year = 2006 | pmid = 16472145 | doi = 10.2174/138161206775474369 | title-link = Grb2 }}

There are at present no drugs on the market specially targeting phosphorylation sites, however, a number of drugs target the kinase domain. This tactic has shown promise in the treatments of various forms of cancer. For example, Stutnet® is a receptor tyrosine kinase (RTK) inhibitor for treating gastrointestinal cancer, Gleevec® specially targets bcr-abl and Sprycel® is a broad-based tyrosine kinase inhibitor whose targets include Bcr-Abl and Src. Cleavage is another process directed by motif recognition with the proteases responsible for cleavage a good drug target. For example, Tritace®, Vasotec®, Accupril®, and Lotensin® are substrate mimetic Angiotensin converting enzymes inhibitors. Other drugs that target post-translational modifications include Zovirax®, an antiviral myristoylation inhibitor and Farnysyl Transferase inhibitors that block the lipidation modification to a CAAX-box motif.

Recommended further reading:{{cite journal | vauthors = Metallo SJ | title = Intrinsically disordered proteins are potential drug targets | journal = Current Opinion in Chemical Biology | volume = 14 | issue = 4 | pages = 481–8 | date = August 2010 | pmid = 20598937 | pmc = 2918680 | doi = 10.1016/j.cbpa.2010.06.169 }}

SLiMs are usually described by regular expressions in the motif literature with the important residues defined based on a combination of experimental, structural and evolutionary evidence. However, high throughput screening such as phage display has seen a large increase in the available information for many motifs classes allowing them to be described with sequence logos.{{cite journal | vauthors = Haslam NJ, Shields DC | title = Profile-based short linear protein motif discovery | journal = BMC Bioinformatics | volume = 13 | pages = 104 | date = May 2012 | pmid = 22607209 | pmc = 3534220 | doi = 10.1186/1471-2105-13-104 | doi-access = free }} Several diverse repositories currently curate the available motif data. In terms of scope, the Eukaryotic Linear Motif resource (ELM){{cite journal | vauthors = Gould CM, Diella F, Via A, Puntervoll P, Gemünd C, Chabanis-Davidson S, Michael S, Sayadi A, Bryne JC, Chica C, Seiler M, Davey NE, Haslam N, Weatheritt RJ, Budd A, Hughes T, Pas J, Rychlewski L, Travé G, Aasland R, Helmer-Citterich M, Linding R, Gibson TJ | display-authors = 6 | title = ELM: the status of the 2010 eukaryotic linear motif resource | journal = Nucleic Acids Research | volume = 38 | issue = Database issue | pages = D167-80 | date = January 2010 | pmid = 19920119 | pmc = 2808914 | doi = 10.1093/nar/gkp1016 }} and MiniMotif Miner (MnM){{cite journal | vauthors = Rajasekaran S, Balla S, Gradie P, Gryk MR, Kadaveru K, Kundeti V, Maciejewski MW, Mi T, Rubino N, Vyas J, Schiller MR | display-authors = 6 | title = Minimotif miner 2nd release: a database and web system for motif search | journal = Nucleic Acids Research | volume = 37 | issue = Database issue | pages = D185-90 | date = January 2009 | pmid = 18978024 | pmc = 2686579 | doi = 10.1093/nar/gkn865 }} represent the two largest motif databases as they attempt to capture all motifs from the available literature. Several more specific and specialised databases also exist, PepCyber{{cite journal | vauthors = Gong W, Zhou D, Ren Y, Wang Y, Zuo Z, Shen Y, Xiao F, Zhu Q, Hong A, Zhou X, Gao X, Li T | display-authors = 6 | title = PepCyber:P~PEP: a database of human protein protein interactions mediated by phosphoprotein-binding domains | journal = Nucleic Acids Research | volume = 36 | issue = Database issue | pages = D679-83 | date = January 2008 | pmid = 18160410 | pmc = 2238930 | doi = 10.1093/nar/gkm854 }} and ScanSite{{cite journal | vauthors = Obenauer JC, Cantley LC, Yaffe MB | title = Scansite 2.0: Proteome-wide prediction of cell signaling interactions using short sequence motifs | journal = Nucleic Acids Research | volume = 31 | issue = 13 | pages = 3635–41 | date = July 2003 | pmid = 12824383 | pmc = 168990 | doi = 10.1093/nar/gkg584 }} focus on smaller subsets of motifs, phosphopeptide binding and important signaling domains respectively. PDZBase{{cite journal | vauthors = Beuming T, Skrabanek L, Niv MY, Mukherjee P, Weinstein H | title = PDZBase: a protein-protein interaction database for PDZ-domains | journal = Bioinformatics | volume = 21 | issue = 6 | pages = 827–8 | date = March 2005 | pmid = 15513994 | doi = 10.1093/bioinformatics/bti098 | doi-access = free }} focuses solely on PDZ domain ligands. MEROPS{{cite journal | vauthors = Rawlings ND, Barrett AJ, Bateman A | title = MEROPS: the peptidase database | journal = Nucleic Acids Research | volume = 38 | issue = Database issue | pages = D227-33 | date = January 2010 | pmid = 19892822 | pmc = 2808883 | doi = 10.1093/nar/gkp971 }} and CutDB{{cite journal | vauthors = Igarashi Y, Eroshkin A, Gramatikova S, Gramatikoff K, Zhang Y, Smith JW, Osterman AL, Godzik A | display-authors = 6 | title = CutDB: a proteolytic event database | journal = Nucleic Acids Research | volume = 35 | issue = Database issue | pages = D546-9 | date = January 2007 | pmid = 17142225 | pmc = 1669773 | doi = 10.1093/nar/gkl813 }} curate available proteolytic event data including protease specificity and cleavage sites. There has been a large increase in the number of publications describing motif mediated interactions over past decade and as a result a large amount of the available literature remains to be curated. Recent work has created the tool MiMosa{{cite journal | vauthors = Vyas J, Nowling RJ, Meusburger T, Sargeant D, Kadaveru K, Gryk MR, Kundeti V, Rajasekaran S, Schiller MR | display-authors = 6 | title = MimoSA: a system for minimotif annotation | journal = BMC Bioinformatics | volume = 11 | pages = 328 | date = June 2010 | pmid = 20565705 | pmc = 2905367 | doi = 10.1186/1471-2105-11-328 | doi-access = free }} to expedite the annotation process and encourage semantically robust motif descriptions.{{cite journal | vauthors = Praefcke GJ, Ford MG, Schmid EM, Olesen LE, Gallop JL, Peak-Chew SY, Vallis Y, Babu MM, Mills IG, McMahon HT | display-authors = 6 | title = Evolving nature of the AP2 alpha-appendage hub during clathrin-coated vesicle endocytosis | journal = The EMBO Journal | volume = 23 | issue = 22 | pages = 4371–83 | date = November 2004 | pmid = 15496985 | pmc = 526462 | doi = 10.1038/sj.emboj.7600445 }}

SLiMs are short and degenerate and as a result the proteome is littered with stochastically occurring peptides that resemble functional motifs. The biologically relevant cellular partners can easily distinguish functional motifs, however computational tools have yet to reach a level of sophistication where motif discovery can be accomplished with high success rates.

Motif discovery tools can be split into two major categories, discovery of novel instance of known functional motifs class and discovery of functional motifs class, however, they all use a limited and overlapping set of attributes to discriminate true and false positives. The main discrimatory attributes used in motif discovery are:

• Accessibility – the motif must be accessible for the binding partner. Intrinsic disorder prediction tools (such as IUPred or GlobPlot), domain databases (such as Pfam and SMART) and experimentally derived structural data (from sources such as PDB) can be used to check the accessibility of predicted motif instances.
• Conservation – the conservation of a motif correlates strongly with functionality and many experimental motifs are seen as islands of strong constraint in regions of weak conservation. Alignment of homologous proteins can be used to calculate conservation metric for a motif.
• Physicochemical properties – Certain intrinsic properties of residues or stretches of amino acids are strong discriminators of functionality, for example, the propensity of a region of disorder to undergo a disorder to order transition.
• Enrichment in groupings of similar proteins – Motif often evolve convergently to carry out similar tasks in different proteins such as mediating binding to a specific partner or targeting proteins to a particular subcellular localisation. Often in such cases these grouping the motif occurs more often than is expected by chance and can be detected by searching for enriched motifs.

The Eukaryotic Linear Motif resource (ELM) and MiniMotif Miner (MnM) both provide servers to search for novel instance of known functional motifs in protein sequences. SLiMSearch allows similar searches on a proteome-wide scale.{{cite journal | vauthors = Davey NE, Haslam NJ, Shields DC, Edwards RJ | title = SLiMSearch 2.0: biological context for short linear motifs in proteins | journal = Nucleic Acids Research | volume = 39 | issue = Web Server issue | pages = W56-60 | date = July 2011 | pmid = 21622654 | pmc = 3125787 | doi = 10.1093/nar/gkr402 }}

More recently computational methods have been developed that can identify new Short Linear Motifs de novo.{{cite journal | vauthors = Hugo W, Song F, Aung Z, Ng SK, Sung WK | title = SLiM on Diet: finding short linear motifs on domain interaction interfaces in Protein Data Bank | journal = Bioinformatics | volume = 26 | issue = 8 | pages = 1036–42 | date = April 2010 | pmid = 20167627 | doi = 10.1093/bioinformatics/btq065 | citeseerx = 10.1.1.720.9626 }} Interactome-based tools rely on identifying a set of proteins that are likely to share a common function, such as binding the same protein or being cleaved by the same peptidase. Two examples of such software are DILIMOT and SLiMFinder.{{cite journal | vauthors = Neduva V, Russell RB | title = DILIMOT: discovery of linear motifs in proteins | journal = Nucleic Acids Research | volume = 34 | issue = Web Server issue | pages = W350-5 | date = July 2006 | pmid = 16845024 | pmc = 1538856 | doi = 10.1093/nar/gkl159 }}{{cite journal | vauthors = Davey NE, Haslam NJ, Shields DC, Edwards RJ | title = SLiMFinder: a web server to find novel, significantly over-represented, short protein motifs | journal = Nucleic Acids Research | volume = 38 | issue = Web Server issue | pages = W534-9 | date = July 2010 | pmid = 20497999 | pmc = 2896084 | doi = 10.1093/nar/gkq440 }} Anchor and α-MoRF-Pred use physicochemical properties to search for motif-like peptides in disordered regions (termed MoRFs, among others). ANCHOR{{cite journal | vauthors = Mészáros B, Simon I, Dosztányi Z | title = Prediction of protein binding regions in disordered proteins | journal = PLOS Computational Biology | volume = 5 | issue = 5 | pages = e1000376 | date = May 2009 | pmid = 19412530 | pmc = 2671142 | doi = 10.1371/journal.pcbi.1000376 | bibcode = 2009PLSCB...5E0376M | editor1-last = Casadio | editor1-first = Rita | doi-access = free }} identifies stretches of intrinsically disordered regions that cannot form favorable intrachain interactions to fold without additional stabilising energy contributed by a globular interaction partner. α-MoRF-Pred{{cite journal | vauthors = Cheng Y, Oldfield CJ, Meng J, Romero P, Uversky VN, Dunker AK | title = Mining alpha-helix-forming molecular recognition features with cross species sequence alignments | journal = Biochemistry | volume = 46 | issue = 47 | pages = 13468–77 | date = November 2007 | pmid = 17973494 | pmc = 2570644 | doi = 10.1021/bi7012273 }} uses the inherent propensity of many SLiM to undergo a disorder to order transition upon binding to discover α-helical forming stretches within disordered regions.

MoRFPred{{cite journal | vauthors = Disfani FM, Hsu WL, Mizianty MJ, Oldfield CJ, Xue B, Dunker AK, Uversky VN, Kurgan L | display-authors = 6 | title = MoRFpred, a computational tool for sequence-based prediction and characterization of short disorder-to-order transitioning binding regions in proteins | journal = Bioinformatics | volume = 28 | issue = 12 | pages = i75-83 | date = June 2012 | pmid = 22689782 | pmc = 3371841 | doi = 10.1093/bioinformatics/bts209 }} and MoRFchibi SYSTEM{{cite journal | vauthors = Malhis N, Gsponer J | title = Computational identification of MoRFs in protein sequences | journal = Bioinformatics | volume = 31 | issue = 11 | pages = 1738–44 | date = June 2015 | pmid = 25637562 | pmc = 4443681 | doi = 10.1093/bioinformatics/btv060 }}{{cite journal | vauthors = Malhis N, Wong ET, Nassar R, Gsponer J | title = Computational Identification of MoRFs in Protein Sequences Using Hierarchical Application of Bayes Rule | journal = PLOS ONE | volume = 10 | issue = 10 | pages = e0141603 | date = 30 October 2015 | pmid = 26517836 | pmc = 4627796 | doi = 10.1371/journal.pone.0141603 | bibcode = 2015PLoSO..1041603M | doi-access = free }}{{cite journal | vauthors = Malhis N, Jacobson M, Gsponer J | title = MoRFchibi SYSTEM: software tools for the identification of MoRFs in protein sequences | journal = Nucleic Acids Research | volume = 44 | issue = W1 | pages = W488-93 | date = July 2016 | pmid = 27174932 | pmc = 4987941 | doi = 10.1093/nar/gkw409 }} are SVM based predictors which utilize multiple features including local sequence physicochemical properties, long stretches of disordered regions and conservation in their predictions. SLiMPred{{cite journal | vauthors = Mooney C, Pollastri G, Shields DC, Haslam NJ | title = Prediction of short linear protein binding regions | journal = Journal of Molecular Biology | volume = 415 | issue = 1 | pages = 193–204 | date = January 2012 | pmid = 22079048 | doi = 10.1016/j.jmb.2011.10.025 | hdl-access = free | hdl = 10197/3395 }} is neural network–based method for the de novo discovery of SLiMs from the protein sequence. Information about the structural context of the motif (predicted secondary structure, structural motifs, solvent accessibility, and disorder) are used during the predictive process. Importantly, no previous knowledge about the protein (i.e., no evolutionary or experimental information) is required.

{{Reflist|2}}

• [http://pawsonlab.mshri.on.ca/index.php?option=com_content&task=view&id=30&Itemid=63 Pawsons Lab Resource on motif-binding domains]

• [http://elm.eu.org/ Eukaryotic Linear Motif Database]
• [http://mnm.engr.uconn.edu/MNM/SMSSearchServlet MiniMotif Miner]
• [http://www.pepcyber.org/PPEP/index.php PepCyber]
• [http://scansite.mit.edu/ ScanSite]

• [http://anchor.enzim.hu/ ANCHOR] {{Webarchive|url=https://web.archive.org/web/20091023051133/http://anchor.enzim.hu/ |date=2009-10-23 }}
• [http://dilimot.russelllab.org/ DiLiMot]
• [http://elm.eu.org/ Eukaryotic Linear Motif Database]
• [http://mnm.engr.uconn.edu/MNM/SMSSearchServlet MiniMotif Miner]
• [http://bioware.ucd.ie/ SLiMSuite] :
• [http://bioware.ucd.ie/~compass/biowareweb/Server_pages/slimpred.php SLiMPred]
• [http://bioware.ucd.ie/~compass/biowareweb/Server_pages/slimfinder.html SLiMFinder]
• [http://bioware.ucd.ie/~compass/biowareweb/Server_pages/slimsearch3.html SLiMSearch]
• [http://bioware.ucd.ie/~compass/biowareweb/Server_pages/comparimotif.html Comparimotif]
• [http://scansite.mit.edu/ ScanSite]

{{MotifBindingDomains}}

Category:Protein structural motifs

Category:Protein domains