Computational survey of peptides derived from disulphide-bonded protein loops that may serve as mediators of protein-protein interactions

BMC Bioinformatics

Fergal J Duffy³  Marc Devocelle²  David R Croucher¹  Denis C Shields³ 

[1] Systems Biology Ireland, University College Dublin, Belfield, Dublin 4 Ireland

[2] Department of Chemistry, Royal College of Surgeons in Ireland, 123 St. Stephens Green, Dublin 2, Ireland

[3] Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4 Ireland

关键词: Ribosomal cyclic peptide;    Bioactive peptide;    Protein interface;    Protein loop;    Cyclic peptide;   

Others  :  1085997
DOI  :  10.1186/1471-2105-15-305

 received in 2014-01-03, accepted in 2014-07-17,  发布年份 2014

【 摘 要 】

Background

Bioactive cyclic peptides derived from natural sources are well studied, particularly those derived from non-ribosomal synthetases in fungi or bacteria. Ribosomally synthesised bioactive disulphide-bonded loops represent a large, naturally enriched library of potential bioactive compounds, worthy of systematic investigation.

Results

We examined the distribution of short cyclic loops on the surface of a large number of proteins, especially membrane or extracellular proteins. Available three-dimensional structures highlighted a number of disulphide-bonded loops responsible for the majority of the likely binding interactions in a variety of protein complexes, due to their location at protein-protein interfaces. We find that disulphide-bonded loops at protein-protein interfaces may, but do not necessarily, show biological activity independent of their parent protein. Examining the conservation of short disulphide bonded loops in proteins, we find a small but significant increase in conservation inside these loops compared to surrounding residues. We identify a subset of these loops that exhibit a high relative conservation, particularly among peptide hormones.

Conclusions

We conclude that short disulphide-bonded loops are found in a wide variety of biological interactions. They may retain biological activity outside their parent proteins. Such structurally independent peptides may be useful as biologically active templates for the development of novel modulators of protein-protein interactions.

【 授权许可】

   
2014 Duffy et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Kotz J: Bringing macrocycles full circle. Science-Business eXchange 2012., 5(45) doi:10.1038/scibx.2012.1176
• [2]Gould A, Ji Y, Aboye LT, Camarero AJ: Cyclotides, a novel ultrastable polypeptide scaffold for drug discovery. Curr Pharm Des 2011, 17(38):4294-4307. doi:10.2174/138161211798999438
• [3]Lehrer RI, Cole AM, Selsted ME: θ-Defensins: cyclic peptides with endless potential. J Biol Chem 2012, 287(32):27014-9. doi:10.1074/jbc.R112.346098
• [4]Hamman JH, Enslin GM, Kotzé AF: Oral delivery of peptide drugs: barriers and developments. BioDrugs : Clin Immunotherapeutics Biopharmaceuticals Gene Ther 2005, 19(3):165-77.
• [5]Xiao Q, Pei D: High-throughput synthesis and screening of cyclic peptide antibiotics. J Med Chem 2007, 50(13):3132-7. doi:10.1021/jm070282e
• [6]Lamberts SW, van der Lely AJ, de Herder WW, Hofland LJ: Octreotide. N Engl J Med 1996, 334(4):246-254. doi:10.1056/NEJM199601253340408
• [7]Schreiber SL, Crabtree GR: The mechanism of action of cyclosporin A and FK506. Immunol Today 1992, 13(4):136-142. doi:10.1016/0167-5699(92)90111-J
• [8]Schwarzer D, Finking R, Marahiel MA: Nonribosomal peptides?: from genes to products. Nat Prod Rep 2003, 20(3):275-287. doi:10.1039/b111145k
• [9]Conlan BF, Gillon AD, Craik DJ, Anderson MA: Circular proteins and mechanisms of cyclization. Biopolymers 2010, 94(5):573-583. doi:10.1002/bip.21422
• [10]Cascales L, Craik DJ: Naturally occurring circular proteins: distribution, biosynthesis and evolution. Org Biomol Chem 2010, 8(22):5035-47. doi:10.1039/c0ob00139b
• [11]Mulvenna JP, Wang C, Craik DJ: CyBase: a database of cyclic protein sequence and structure. Nucleic Acids Res 2006, 34(Database issue):192-4. doi:10.1093/nar/gkj005
• [12]Wang CKL, Kaas Q, Chiche L, Craik DJ: CyBase: a database of cyclic protein sequences and structures, with applications in protein discovery and engineering. Nucleic Acids Res 2008, 36(Database issue):206-10. doi:10.1093/nar/gkm953
• [13]Toniolo C: Intramolecularly hydrogen-bonded peptide conformations. CRC Crit Rev Biochem 1980, 9(1):1-44.
• [14]Bisang C, Weber C, Robinson JA: Protein-loop mimetics: a diketopiperazine-based template to stabilize loop conformations in cyclic peptides containing the NPNA and RGD motifs. Helvetica Chimica Acta 1996, 79(7):1825-1842. doi:10.1002/hlca.19960790708
• [15]Gunasekaran K, Ramakrishnan C, Balaram P: Beta-hairpins in proteins revisited: lessons for de novo design. Protein Eng Des Select 1997, 10(10):1131-1141. doi:10.1093/protein/10.10.1131
• [16]Cochran AG, Tong RT, Starovasnik MA, Park EJ, McDowell RS, Theaker JE, Skelton NJ: A minimal peptide scaffold for β-turn display: optimizing a strand position in disulfide-cyclized β-hairpins. J Am Chem Soc 2001, 123(4):625-632. doi:10.1021/ja003369x
• [17]London N, Raveh B, Movshovitz-Attias D, Schueler-Furman O: Can self-inhibitory peptides be derived from the interfaces of globular protein-protein interactions? Proteins 2010, 78(15):3140-9. doi:10.1002/prot.22785
• [18]Xu Y, Rahman NaBD, Othman R, Hu P, Huang M: Computational identification of self-inhibitory peptides from envelope proteins. Proteins 2012, 80(9):2154-68. doi:10.1002/prot.24105
• [19]Dechantsreiter MA, Planker E, Mathä B, Lohof E, Hölzemann G, Jonczyk A, Goodman SL, Kessler H: N-Methylated cyclic RGD peptides as highly active and selective alpha(V)beta3 integrin antagonists. J Med Chem 1999, 42(16):3033-40. doi:10.1021/jm970832g
• [20]Edwards RJ, Moran N, Devocelle M, Kiernan A, Meade G, Signac W, Foy M, Park SDE, Dunne E, Kenny D, Shields DC: Bioinformatic discovery of novel bioactive peptides. Nat Chem Biol 2007, 3(2):108-112.
• [21]Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The protein data bank. Nucleic Acids Res 2000, 28(1):235-242.
• [22]Schrodinger LLC: The PyMOL Molecular Graphics System, Version 1.3r1. 2010. [ http://www.pymol.org/citing webcite]
• [23]Cukuroglu E, Gursoy A, Keskin O: HotRegion: a database of predicted hot spot clusters. Nucleic Acids Res 2012, 40(Database issue):829-33. doi:10.1093/nar/gkr929
• [24]Nguyen VD, Hatahet F, Salo KEH, Enlund E, Zhang C, Ruddock LW: Pre-expression of a sulfhydryl oxidase significantly increases the yields of eukaryotic disulfide bond containing proteins expressed in the cytoplasm of E.coli. Microbial Cell Fact 2011, 10:1. doi:10.1186/1475-2859-10-1 BioMed Central Full Text
• [25]Maupetit J, Derreumaux P, Tufféry P: A fast method for large-scale de novo peptide and miniprotein structure prediction. J Comput Chem 2010, 31(4):726-38. doi:10.1002/jcc.21365
• [26]Kihara D, Chen H, Yang YD: Quality assessment of protein structure models. Cur Prot Pept Sci 2009, 10(3):216-28.
• [27]Abergel C, Monchois V, Byrne D, Chenivesse S, Lembo F, Lazzaroni J-C, Claverie J-M: Structure and evolution of the Ivy protein family, unexpected lysozyme inhibitors in Gram-negative bacteria. Proc Natl Acad Sci U S A 2007, 104(15):6394-9. doi:10.1073/pnas.0611019104
• [28]Kim HM, Park BS, Kim J-I, Kim SE, Lee J, Oh SC, Enkhbayar P, Matsushima N, Lee H, Yoo OJ, Lee J-O: Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran. Cell 2007, 130(5):906-17. doi:10.1016/j.cell.2007.08.002
• [29]Zhou A, Huntington JA, Pannu NS, Carrell RW, Read RJ: How vitronectin binds PAI-1 to modulate fibrinolysis and cell migration. Nat Rev Urol 2003, 10(7):541-4. doi:10.1038/nsb943
• [30]Huai Q, Zhou A, Lin L, Mazar AP, Parry GC, Callahan J, Shaw DE, Furie B, Furie BC, Huang M: Crystal structures of two human vitronectin, urokinase and urokinase receptor complexes. Nat Struct Mol Biol 2008, 15(4):422-3. doi:10.1038/nsmb.1404
• [31]Alfano D, Franco P, Vocca I, Gambi N, Pisa V, Mancini A, Caputi M, Carriero MV, Iaccarino I, Stoppelli MP: The urokinase plasminogen activator and its receptor: role in cell growth and apoptosis. Thromb Haemost 2005, 93(2):205-11. doi:10.1267/THRO05020205
• [32]Sidenius N, Blasi F: The urokinase plasminogen activator system in cancer: recent advances and implication for prognosis and therapy. Cancer Metastasis Rev 2003, 22(2-3):205-22. doi:10.1023/A:1023099415940
• [33]Ogiso H, Ishitani R, Nureki O, Fukai S, Yamanaka M, Kim J-H, Saito K, Sakamoto A, Inoue M, Shirouzu M, Yokoyama S: Crystal structure of the complex of human epidermal growth factor and receptor extracellular domains. Cell 2002, 110(6):775-787. doi:10.1016/S0092-8674(02)00963-7
• [34]Luckett S, Garcia RS, Barker JJ, Konarev AV, Shewry PR, Clarke AR, Brady RL: High-resolution structure of a potent, cyclic proteinase inhibitor from sunflower seeds. J Mol Biol 1999, 290(2):525-33. doi:10.1006/jmbi.1999.2891
• [35]Domingo GJ, Leatherbarrow RJ, Freeman N, Patel S, Weir M: Synthesis of a mixture of cyclic peptides based on the Bowman-Birk reactive site loop to screen for serine protease inhibitors. Int J Pept Protein Res 1995, 46(1):79-87. doi:10.1111/j.1399-3011.1995.tb00585.x
• [36]Linggi B, Carpenter G: ErbB receptors: new insights on mechanisms and biology. Trends Cell Biol 2006, 16(12):649-56. doi:10.1016/j.tcb.2006.10.008
• [37]Sun YQ: Glycine residues provide flexibility for enzyme active sites. J Biol Chem 1997, 272(6):3190-3194. doi:10.1074/jbc.272.6.3190
• [38]Jacob J, Duclohier H, Cafiso DS: The role of proline and glycine in determining the backbone flexibility of a channel-forming peptide. Biophys J 1999, 76(3):1367-76. doi:10.1016/S0006-3495(99)77298-X
• [39]Edwards RJ: GOPHER: Generation of Orthologous Proteins from High-throughput Evolutionary Relationships. 2006. [ http://bioware.ucd.ie/~compass/biowareweb/ webcite]
• [40]Edgar RC: MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res 2004, 32(5):1792-7. doi:10.1093/nar/gkh340
• [41]Capra JA, Singh M: Predicting functionally important residues from sequence conservation. Bioinformatics (Oxford, England) 2007, 23(15):1875-82. doi:10.1093/bioinformatics/btm270
• [42]Cygler M, Schrag JD, Sussman JL, Harel M, Silman I, Gentry MK, Doctor BP: Relationship between sequence conservation and three-dimensional structure in a large family of esterases, lipases, and related proteins. Prot Sci : Publication Prot Soc 1993, 2(3):366-82. doi:10.1002/pro.5560020309
• [43]Bustamante CD, Townsend JP, Hartl DL: Solvent accessibility and purifying selection within proteins of Escherichia coli and Salmonella enterica. Mol Biol Evol 2000, 17(2):301-8.
• [44]Yeh S-W, Liu J-W, Yu S-H, Shih C-H, Hwang J-K, Echave J: Site-specific structural constraints on protein sequence evolutionary divergence: local packing density versus solvent exposure. Mol Biol Evol 2014, 31(1):135-9. doi:10.1093/molbev/mst178
• [45]Woolhouse MEJ, Webster JP, Domingo E, Charlesworth B, Levin BR: Biological and biomedical implications of the co-evolution of pathogens and their hosts. Nat Genet 2002, 32(4):569-77. doi:10.1038/ng1202-569
• [46]Shimaoka M, Takagi J, Springer Ta: Conformational regulation of integrin structure and function. Annu Rev Biophys Biomol Struct 2002, 31:485-516. doi:10.1146/annurev.biophys.31.101101.140922
• [47]Gould CM, Diella F, Via A, Puntervoll P, Gemund 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, Trave G, Aasland R, Helmer-Citterich M, Linding R, Gibson TJ: ELM: the status of the 2010 eukaryotic linear motif resource. Nucleic Acids Res 2010, 38(Database issue):167-80. doi:10.1093/nar/gkp1016
• [48]Haslam NJ, Shields DC: Peptide-binding domains: are limp handshakes safest? Sci Signal 2012, 5(243):40. doi:10.1126/scisignal.2003372
• [49]Metz A, Pfleger C, Kopitz H, Pfeiffer-Marek S, Baringhaus K-H, Gohlke H: Hot spots and transient pockets: predicting the determinants of small-molecule binding to a protein-protein interface. J Chem Inf Model 2012, 52(1):120-33. doi:10.1021/ci200322s
• [50]Kennedy AR, Davis JG, Carlton W, Ware JH: Effects of dietary antioxidant supplementation on the development of malignant lymphoma and other neoplastic lesions in mice exposed to proton or iron-ion radiation. Radiat Res 2008, 169(6):615-25. doi:10.1667/RR1296.1
• [51]Nguyen LT, Chau JK, Perry Na, de Boer L, Zaat SaJ, Vogel HJ: Serum stabilities of short tryptophan- and arginine-rich antimicrobial peptide analogs. PloS one 2010, 5(9):11-18. doi:10.1371/journal.pone.0012684
• [52]Murakami N, Tamura S, Wang W, Takagi T, Kobayashi M: Synthesis of stable analogs in blood and conformational analysis of arenastatin A, a potent cytotoxic spongean depsipeptide. Tetrahedron 2001, 57(20):4323-4336. doi:10.1016/S0040-4020(01)00339-8
• [53]Werle M, Bernkop-Schnürch A: Strategies to improve plasma half life time of peptide and protein drugs. Amino Acids 2006, 30(4):351-67. doi:10.1007/s00726-005-0289-3
• [54]Baú D, Martin AJM, Mooney C, Vullo A, Walsh I, Pollastri G: Distill: a suite of web servers for the prediction of one-, two- and three-dimensional structural features of proteins. BMC Bioinformatics 2006, 7:402. doi:10.1186/1471-2105-7-402 BioMed Central Full Text
• [55]Cock PJ, Antao T, Chang JT, Chapman BA, Cox CJ, Dalke A, Friedberg I, Hamelryck T, Kauff F, Wilczynski B, de Hoon MJ: Biopython: freely available Python tools for computational molecular biology and bioinformatics. Bioinformatics 2009, 25(11):1422-1423. doi:10.1093/bioinformatics/btp163
• [56]Chatr-aryamontri A, Ceol A, Palazzi LM, Nardelli G, Schneider MV, Castagnoli L, Cesareni G: MINT: the Molecular INTeraction database. Nucleic Acids Res 2007, 35(Database issue):572-4. doi:10.1093/nar/gkl950
• [57]Navratil V, de Chassey B, Meyniel L, Delmotte S, Gautier C, André P, Lotteau V, Rabourdin-Combe C: VirHostNet: a knowledge base for the management and the analysis of proteome-wide virus-host interaction networks. Nucleic Acids Res 2009, 37(Database issue):661-8. doi:10.1093/nar/gkn794
• [58]Chatr-Aryamontri A, Breitkreutz B-J, Heinicke S, Boucher L, Winter A, Stark C, Nixon J, Ramage L, Kolas N, O’Donnell L, Reguly T, Breitkreutz A, Sellam A, Chen D, Chang C, Rust J, Livstone M, Oughtred R, Dolinski K, Tyers M: The BioGRID interaction database 2013 update. Nucleic Acids Res 2013, 41(Database issue):816-23. doi:10.1093/nar/gks1158