Functional repertoire, molecular pathways and diseases associated with 3D domain swapping in the human proteome

Journal of Clinical Bioinformatics

Ramanathan Sowdhamini²  Khader Shameer¹ 

[1] Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN 55905, USA;National Centre for Biological Sciences (TIFR), GKVK Campus, Bangalore 560065, India

关键词: Biological data mining;    Data integration;    Human proteome;    Deposition disease;    Human disease;    Protein aggregation;   

Others  :  805927
DOI  :  10.1186/2043-9113-2-8

 received in 2011-12-16, accepted in 2012-04-03,  发布年份 2012

【 摘 要 】

Background

3D domain swapping is a novel structural phenomenon observed in diverse set of protein structures in oligomeric conformations. A distinct structural feature, where structural segments in a protein dimer or higher oligomer were shared between two or more chains of a protein structure, characterizes 3D domain swapping. 3D domain swapping was observed as a key mediator of numerous functional mechanisms and play pathogenic role in various diseases including conformational diseases like amyloidosis, Alzheimer's disease, Parkinson's disease and prion diseases. We report the first study with a focus on identifying functional classes, pathways and diseases mediated by 3D domain swapping in the human proteome.

Methods

We used a panel of four enrichment tools with two different ontologies and two annotations database to derive biological and clinical relevant information associated with 3D domain swapping. Protein domain enrichment analysis followed by Gene Ontology (GO) term enrichment analysis revealed the functional repertoire of proteins involved in swapping. Pathway analysis using KEGG annotations revealed diverse pathway associations of human proteins involved in 3D domain swapping. Disease Ontology was used to find statistically significant associations with proteins in swapped conformation and various disease categories (P-value < 0.05).

Results

We report meta-analysis results of a literature-curated dataset of human gene products involved in 3D domain swapping and discuss new insights about the functional repertoire, pathway associations and disease implications of proteins involved in 3D domain swapping.

Conclusions

Our integrated bioinformatics pipeline comprising of four different enrichment tools, two ontologies and two annotations revealed new insights into the functional and disease correlations with 3D domain swapping. GO term enrichment were used to infer terms associated with three different GO categories. Protein domain enrichment was used to identify conserved domains enriched in swapped proteins. Pathway enrichment analysis using KEGG annotations revealed that proteins with swapped conformations are present in all six classes of KEGG BRITE hierarchy and significantly enriched KEGG pathways were observed in five classes. Five major classes of disease were found to be associated with 3D domain swapping using functional disease ontology based enrichment analysis. Five classes of human diseases: cancer, diseases of the respiratory or pulmonary system, degenerative diseases of the central nervous system, vascular disease and encephalitis were found to be significant. In conclusion, our study shows that bioinformatics based analytical approaches using curated data can enhance the understanding of functional and disease implications of 3D domain swapping.

【 授权许可】

   
2012 Shameer and Sowdhamini; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]May AC, Johnson MS, Rufino SD, Wako H, Zhu ZY, Sowdhamini R, Srinivasan N, Rodionov MA, Blundell TL: The recognition of protein structure and function from sequence: adding value to genome data. Philos Trans R Soc Lond B Biol Sci 1994, 344(1310):373-381.
• [2]Holm L, Sander C: Mapping the protein universe. Science 1996, 273(5275):595-603.
• [3]Grant A, Lee D, Orengo C: Progress towards mapping the universe of protein folds. Genome Biol 2004, 5(5):107.. BioMed Central Full Text
• [4]Reddy Chilamakuri CS, Sekhar SK, Bernard Offmann, Sowdhamini Ramanathan: PURE: a web server for querying the relationship between pre-existing domains and unassigned regions in proteins. Nature Protocol Exchange 2007. doi:10.1038/nprot.2007.486
• [5]Murzin AG, Brenner SE, Hubbard T, Chothia C: SCOP: a structural classification of proteins database for the investigation of sequences and structures. J Mol Biol 1995, 247(4):536-540.
• [6]Andreeva A, Howorth D, Chandonia JM, Brenner SE, Hubbard TJ, Chothia C, Murzin AG: Data growth and its impact on the SCOP database: new developments. Nucleic Acids Res 2008, (36 Database):D419-425.
• [7]Nooren IM, Thornton JM: Diversity of protein-protein interactions. EMBO J 2003, 22(14):3486-3492.
• [8]Nooren IM, Thornton JM: Structural Characterisation and Functional Significance of Transient Protein-Protein Interactions. J Mol Biol 2003, 325(5):991-1018.
• [9]Jones S, Thornton JM: Principles of protein-protein interactions. Proc Natl Acad Sci USA 1996, 93(1):13-20.
• [10]Jones S, Marin A, Thornton JM: Protein domain interfaces: characterization and comparison with oligomeric protein interfaces. Protein Eng 2000, 13(2):77-82.
• [11]Shameer K, Pugalenthi G, Kandaswamy KK, Sowdhamini R: 3dswap-pred: Prediction of 3D Domain Swapping from Protein Sequence Using Random Forest Approach. Protein Pept Lett 2011, 18(10):1010-20.
• [12]Ding F, Prutzman KC, Campbell SL, Dokholyan NV: Topological determinants of protein domain swapping. Structure 2006, 14(1):5-14.
• [13]Dehouck Y, Biot C, Gilis D, Kwasigroch JM, Rooman M: Sequence-structure signals of 3D domain swapping in proteins. J Mol Biol 2003, 330(5):1215-1225.
• [14]Bennett MJ, Sawaya MR, Eisenberg D: Deposition diseases and 3D domain swapping. Structure 2006, 14(5):811-824.
• [15]Janowski R, Kozak M, Abrahamson M, Grubb A, Jaskolski M: 3D domain-swapped human cystatin C with amyloidlike intermolecular beta-sheets. Proteins 2005, 61(3):570-578.
• [16]Yamasaki M, Li W, Johnson DJ, Huntington JA: Crystal structure of a stable dimer reveals the molecular basis of serpin polymerization. Nature 2008, 455(7217):1255-1258.
• [17]Bennett MJ, Choe S, Eisenberg D: Domain swapping: entangling alliances between proteins. Proc Natl Acad Sci USA 1994, 91(8):3127-3131.
• [18]Bennett MJ, Schlunegger MP, Eisenberg D: 3D domain swapping: a mechanism for oligomer assembly. Protein Sci 1995, 4(12):2455-2468.
• [19]Heringa J, Taylor WR: Three-dimensional domain duplication, swapping and stealing. Curr Opin Struct Biol 1997, 7(3):416-421.
• [20]Gouldson PR, Snell CR, Bywater RP, Higgs C, Reynolds CA: Domain swapping in G-protein coupled receptor dimers. Protein Eng 1998, 11(12):1181-1193.
• [21]Balciunas D, Ronne H: Evidence of domain swapping within the jumonji family of transcription factors. Trends Biochem Sci 2000, 25(6):274-276.
• [22]Ostermeier M, Benkovic SJ: Evolution of protein function by domain swapping. Adv Protein Chem 2000, 55:29-77.
• [23]Jaskolski M: 3D domain swapping, protein oligomerization, and amyloid formation. Acta Biochim Pol 2001, 48(4):807-827.
• [24]Schymkowitz JW, Rousseau F, Wilkinson HR, Friedler A, Itzhaki LS: Observation of signal transduction in three-dimensional domain swapping. Nat Struct Biol 2001, 8(10):888-892.
• [25]Hakansson M, Linse S: Protein reconstitution and 3D domain swapping. Curr Protein Pept Sci 2002, 3(6):629-642.
• [26]Liu Y, Eisenberg D: 3D domain swapping: as domains continue to swap. Protein Sci 2002, 11(6):1285-1299.
• [27]Rousseau F, Schymkowitz JW, Itzhaki LS: The unfolding story of three-dimensional domain swapping. Structure 2003, 11(3):243-251.
• [28]Bennett MJ, Eisenberg D: The evolving role of 3D domain swapping in proteins. Structure 2004, 12(8):1339-1341.
• [29]Sanejouand YH: Domain swapping of CD4 upon dimerization. Proteins 2004, 57(1):205-212.
• [30]Yang S, Cho SS, Levy Y, Cheung MS, Levine H, Wolynes PG, Onuchic JN: Domain swapping is a consequence of minimal frustration. Proc Natl Acad Sci USA 2004, 101(38):13786-13791.
• [31]Kingston RL, Vogt VM: Domain swapping and retroviral assembly. Mol Cell 2005, 17(2):166-167.
• [32]Yang S, Levine H, Onuchic JN, Cox DL: Structure of infectious prions: stabilization by domain swapping. FASEB J 2005, 19(13):1778-1782.
• [33]Gronenborn AM: Protein acrobatics in pairs-dimerization via domain swapping. Curr Opin Struct Biol 2009, 19(1):39-49.
• [34]Chahine J, Cheung MS: Computational studies of the reversible domain swapping of p13suc1. Biophys J 2005, 89(4):2693-2700.
• [35]Cho SS, Levy Y, Onuchic JN, Wolynes PG: Overcoming residual frustration in domain-swapping: the roles of disulfide bonds in dimerization and aggregation. Phys Biol 2005, 2(2):S44-S55.
• [36]Esposito L, Daggett V: Insight into ribonuclease A domain swapping by molecular dynamics unfolding simulations. Biochemistry 2005, 44(9):3358-3368.
• [37]Picone D, Di Fiore A, Ercole C, Franzese M, Sica F, Tomaselli S, Mazzarella L: The role of the hinge loop in domain swapping. The special case of bovine seminal ribonuclease. J Biol Chem 2005, 280(14):13771-13778.
• [38]Seeliger MA, Spichty M, Kelly SE, Bycroft M, Freund SM, Karplus M, Itzhaki LS: Role of conformational heterogeneity in domain swapping and adapter function of the Cks proteins. J Biol Chem 2005, 280(34):30448-30459.
• [39]Yang S, Levine H, Onuchic JN: Protein oligomerization through domain swapping: role of inter-molecular interactions and protein concentration. J Mol Biol 2005, 352(1):202-211.
• [40]Guo Z, Eisenberg D: Runaway domain swapping in amyloid-like fibrils of T7 endonuclease I. Proc Natl Acad Sci USA 2006, 103(21):8042-8047.
• [41]O'Neill JW, Manion MK, Maguire B, Hockenbery DM: BCL-XL dimerization by three-dimensional domain swapping. J Mol Biol 2006, 356(2):367-381.
• [42]Benfield AP, Whiddon BB, Clements JH, Martin SF: Structural and energetic aspects of Grb2-SH2 domain-swapping. Arch Biochem Biophys 2007, 462(1):47-53.
• [43]Wahlbom M, Wang X, Lindstrom V, Carlemalm E, Jaskolski M, Grubb A: Fibrillogenic oligomers of human cystatin C are formed by propagated domain swapping. J Biol Chem 2007, 282(25):18318-18326.
• [44]Garcia-Pino A, Martinez-Rodriguez S, Wahni K, Wyns L, Loris R, Messens J: Coupling of Domain Swapping to Kinetic Stability in a Thioredoxin Mutant. J Mol Biol 2008, 385(5):1590-1599.
• [45]Malevanets A, Sirota FL, Wodak SJ: Mechanism and energy landscape of domain swapping in the B1 domain of protein G. J Mol Biol 2008, 382(1):223-235.
• [46]Park SH, Park HY, Sohng JK, Lee HC, Liou K, Yoon YJ, Kim BG: Expanding substrate specificity of GT-B fold glycosyltransferase via domain swapping and high-throughput screening. Biotechnol Bioeng 2009, 102(4):988-94.
• [47]Sirota FL, Hery-Huynh S, Maurer-Stroh S, Wodak SJ: Role of the amino acid sequence in domain swapping of the B1 domain of protein G. Proteins 2008, 72(1):88-104.
• [48]Hansen EH, Osmani SA, Kristensen C, Moller BL, Hansen J: Substrate specificities of family 1 UGTs gained by domain swapping. Phytochemistry 2009, 70(4):473-482.
• [49]Pesenti ME, Spinelli S, Bezirard V, Briand L, Pernollet JC, Campanacci V, Tegoni M, Cambillau C: Queen bee pheromone binding protein pH-induced domain swapping favors pheromone release. J Mol Biol 2009, 390(5):981-990.
• [50]Miller KH, Karr JR, Marqusee S: A hinge region cis-proline in ribonuclease A acts as a conformational gatekeeper for C-terminal domain swapping. J Mol Biol 2010, 400(3):567-578.
• [51]Orlikowska M, Jankowska E, Kolodziejczyk R, Jaskolski M, Szymanska A: Hinge-loop mutation can be used to control 3D domain swapping and amyloidogenesis of human cystatin C. J Struct Biol 2010, 173(2):406-13.
• [52]Shameer K, Pugalenthi G, Kandaswamy KK, Suganthan PN, Archunan G, Sowdhamini R: Insights into Protein Sequence and Structure-Derived Features Mediating 3D Domain Swapping Mechanism using Support Vector Machine Based Approach. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2901629/] webciteBioinformatics and Biology Insights 2010, 4(4):33-42.
• [53]Shameer K, Shingate PN, Manjunath SC, Karthika M, Pugalenthi G, Sowdhamini R: 3DSwap: curated knowledgebase of proteins involved in 3D domain swapping. [http://database.oxfordjournals.org/content/2011/bar042.full] webciteDatabase (Oxford) 2011., 2011
• [54]da Huang W, Sherman BT, Lempicki RA: Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res 2009, 37(1):1-13.
• [55]Tipney H, Hunter L: An introduction to effective use of enrichment analysis software. Hum Genomics 2010, 4(3):202-206. BioMed Central Full Text
• [56]Finn RD, Mistry J, Tate J, Coggill P, Heger A, Pollington JE, Gavin OL, Gunasekaran P, Ceric G, Forslund K, et al.: The Pfam protein families database. Nucleic Acids Res 2010, 38(Database issue):D211-222.
• [57]Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT: Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 2000, 25(1):25-29.
• [58]Barrell D, Dimmer E, Huntley RP, Binns D, O'Donovan C, Apweiler R: The GOA database in 2009--an integrated Gene Ontology Annotation resource. Nucleic Acids Res 2009, 37(Database issue):D396-403.
• [59]Rhee SY, Wood V, Dolinski K, Draghici S: Use and misuse of the gene ontology annotations. Nat Rev Genet 2008, 9(7):509-515.
• [60]Kanehisa M, Goto S: KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res 2000, 28(1):27-30.
• [61]Du P, Feng G, Flatow J, Song J, Holko M, Kibbe WA, Lin SM: From disease ontology to disease-ontology lite: statistical methods to adapt a general-purpose ontology for the test of gene-ontology associations. Bioinformatics 2009, 25(12):i63-i68.
• [62]Osborne JD, Flatow J, Holko M, Lin SM, Kibbe WA, Zhu LJ, Danila MI, Feng G, Chisholm RL: Annotating the human genome with Disease Ontology. BMC Genomics 2009, 10(Suppl 1):S6. BioMed Central Full Text
• [63]Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, et al.: Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 2005, 102(43):15545-15550.
• [64]Maere S, Heymans K, Kuiper M: BiNGO: a Cytoscape plugin to assess overrepresentation of gene ontology categories in biological networks. Bioinformatics 2005, 21(16):3448-3449.
• [65]Berriz GF, King OD, Bryant B, Sander C, Roth FP: Characterizing gene sets with FuncAssociate. Bioinformatics 2003, 19(18):2502-2504.
• [66]Draghici S, Khatri P, Bhavsar P, Shah A, Krawetz SA, Tainsky MA: Onto-Tools, the toolkit of the modern biologist: Onto-Express, Onto-Compare, Onto-Design and Onto-Translate. Nucleic Acids Res 2003, 31(13):3775-3781.
• [67]Khatri P, Draghici S, Ostermeier GC, Krawetz SA: Profiling gene expression using onto-express. Genomics 2002, 79(2):266-270.
• [68]Bauer S, Grossmann S, Vingron M, Robinson PN: Ontologizer 2.0-a multifunctional tool for GO term enrichment analysis and data exploration. Bioinformatics 2008, 24(14):1650-1651.
• [69]Alexa A, Rahnenfuhrer J, Lengauer T: Improved scoring of functional groups from gene expression data by decorrelating GO graph structure. Bioinformatics 2006, 22(13):1600-1607.
• [70]Molecular Signatures Database [http://www.broadinstitute.org/gsea/msigdb/index.jsp] webcite
• [71]Al-Shahrour F, Diaz-Uriarte R, Dopazo J: FatiGO: a web tool for finding significant associations of Gene Ontology terms with groups of genes. Bioinformatics 2004, 20(4):578-580.
• [72]Newman JC, Weiner AM: L2L: a simple tool for discovering the hidden significance in microarray expression data. Genome Biol 2005, 6(9):R81..
• [73]Zhong S, Storch KF, Lipan O, Kao MC, Weitz CJ, Wong WH: GoSurfer: a graphical interactive tool for comparative analysis of large gene sets in Gene Ontology space. Appl Bioinformatics 2004, 3(4):261-264.
• [74]Masseroli M, Galati O, Pinciroli F: GFINDer: genetic disease and phenotype location statistical analysis and mining of dynamically annotated gene lists. [http://nar.oxfordjournals.org/content/33/suppl_2/W717.full] webciteNucleic Acids Res 2005, (33 Web Server):W717-723.
• [75]Cantor RM, Lange K, Sinsheimer JS: Prioritizing GWAS results: A review of statistical methods and recommendations for their application. Am J Hum Genet 2010, 86(1):6-22.
• [76]Moore JH, Asselbergs FW, Williams SM: Bioinformatics challenges for genome-wide association studies. Bioinformatics 2010, 26(4):445-455.
• [77]Letunic I, Doerks T, Bork P: SMART 6: recent updates and new developments. [http:/ / ukpmc.ac.uk/ articles/ PMC2686533/ / reload=0;jsessionid=WBactjswkZTve9J hiOKX.12] webciteNucleic Acids Res 2009, (37 Database):D229-D232.
• [78]Salomonis N, Hanspers K, Zambon AC, Vranizan K, Lawlor SC, Dahlquist KD, Doniger SW, Stuart J, Conklin BR, Pico AR: GenMAPP 2: new features and resources for pathway analysis. BMC Bioinforma 2007, 8:217. BioMed Central Full Text
• [79]Hamosh A, Scott AF, Amberger JS, Bocchini CA, McKusick VA: Online Mendelian Inheritance in Man (OMIM), a knowledgebase of human genes and genetic disorders. Nucleic Acids Res 2005, 33(Database issue):D514-D517.
• [80]Smith B, Ashburner M, Rosse C, Bard J, Bug W, Ceusters W, Goldberg LJ, Eilbeck K, Ireland A, Mungall CJ, et al.: The OBO Foundry: coordinated evolution of ontologies to support biomedical data integration. Nat Biotechnol 2007, 25(11):1251-1255.
• [81]da Huang W, Sherman BT, Lempicki RA: Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 2009, 4(1):44-57.
• [82]Cote RG, Jones P, Martens L, Kerrien S, Reisinger F, Lin Q, Leinonen R, Apweiler R, Hermjakob H: The Protein Identifier Cross-Referencing (PICR) service: reconciling protein identifiers across multiple source databases. BMC Bioinforma 2007, 8:401. BioMed Central Full Text
• [83]Li C, Li X, Miao Y, Wang Q, Jiang W, Xu C, Li J, Han J, Zhang F, Gong B, et al.: SubpathwayMiner: a software package for flexible identification of pathways. Nucleic Acids Res 2009, 37(19):e131.
• [84]Grossmann S, Bauer S, Robinson PN, Vingron M: Improved detection of overrepresentation of Gene-Ontology annotations with parent child analysis. Bioinformatics 2007, 23(22):3024-3031.
• [85]GeneRIF -- Gene Reference Into Function [http://www.ncbi.nlm.nih.gov/projects/GeneRIF/] webcite
• [86]Hanks SK, Quinn AM, Hunter T: The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science 1988, 241(4861):42-52.
• [87]Rawlings ND, Barrett AJ: Evolution of proteins of the cystatin superfamily. J Mol Evol 1990, 30(1):60-71.
• [88]Kobe B, Deisenhofer J: The leucine-rich repeat: a versatile binding motif. Trends Biochem Sci 1994, 19(10):415-421.
• [89]Stehle T, Schulz GE: Refined structure of the complex between guanylate kinase and its substrate GMP at 2.0 A resolution. J Mol Biol 1992, 224(4):1127-1141.
• [90]Smith DK, Xue H: Sequence profiles of immunoglobulin and immunoglobulin-like domains. J Mol Biol 1997, 274(4):530-545.
• [91]Goh KI, Cusick ME, Valle D, Childs B, Vidal M, Barabasi AL: The human disease network. Proc Natl Acad Sci USA 2007, 104(21):8685-8690.
• [92]Barabasi AL, Gulbahce N, Loscalzo J: Network medicine: a network-based approach to human disease. Nat Rev Genet 2011, 12(1):56-68.
• [93]Vidal M, Cusick ME, Barabasi AL: Interactome networks and human disease. Cell 2011, 144(6):986-998.
• [94]Ashley EA, Butte AJ, Wheeler MT, Chen R, Klein TE, Dewey FE, Dudley JT, Ormond KE, Pavlovic A, Morgan AA, et al.: Clinical assessment incorporating a personal genome. Lancet 2010, 375(9725):1525-1535.
• [95]Thomas PJ, Qu BH, Pedersen PL: Defective protein folding as a basis of human disease. Trends Biochem Sci 1995, 20(11):456-459.
• [96]Prusiner SB: Molecular biology and pathogenesis of prion diseases. Trends Biochem Sci 1996, 21(12):482-487.
• [97]Buxbaum JN: Diseases of protein conformation: what do in vitro experiments tell us about in vivo diseases? Trends Biochem Sci 2003, 28(11):585-592.
• [98]Soto C, Estrada L, Castilla J: Amyloids, prions and the inherent infectious nature of misfolded protein aggregates. Trends Biochem Sci 2006, 31(3):150-155.
• [99]Blundell TL, Jhoti H, Abell C: High-throughput crystallography for lead discovery in drug design. Nat Rev Drug Discov 2002, 1(1):45-54.
• [100]Blundell TL, Sibanda BL, Montalvao RW, Brewerton S, Chelliah V, Worth CL, Harmer NJ, Davies O, Burke D: Structural biology and bioinformatics in drug design: opportunities and challenges for target identification and lead discovery. Philos Trans R Soc Lond B Biol Sci 2006, 361(1467):413-423.
• [101]Zhang S, Zhong N, Xue F, Kang X, Ren X, Chen J, Jin C, Lou Z, Xia B: Three-dimensional domain swapping as a mechanism to lock the active conformation in a super-active octamer of SARS-CoV main protease. Protein Cell 2010, 1(4):371-383.
• [102]Mestres J: Representativity of target families in the Protein Data Bank: impact for family-directed structure-based drug discovery. Drug Discov Today 2005, 10(23-24):1629-1637.
• [103]Stewart L, Clark R, Behnke C: High-throughput crystallization and structure determination in drug discovery. Drug Discov Today 2002, 7(3):187-196.
• [104]Hillisch A, Pineda LF, Hilgenfeld R: Utility of homology models in the drug discovery process. Drug Discov Today 2004, 9(15):659-669.