The ubiquilin gene family: evolutionary patterns and functional insights

BMC Evolutionary Biology

Ignacio Marín¹ 

[1]Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Científicas (IBV-CSIC), Valencia, Spain

关键词: Neurodegeneration;    Gene duplication;    Ubiquitin receptors;    Spermiogenesis;    Ubiquitination;   

Others  :  857542
DOI  :  10.1186/1471-2148-14-63

 received in 2013-09-26, accepted in 2014-03-17,  发布年份 2014

【 摘 要 】

Background

Ubiquilins are proteins that function as ubiquitin receptors in eukaryotes. Mutations in two ubiquilin-encoding genes have been linked to the genesis of neurodegenerative diseases. However, ubiquilin functions are still poorly understood.

Results

In this study, evolutionary and functional data are combined to determine the origin and diversification of the ubiquilin gene family and to characterize novel potential roles of ubiquilins in mammalian species, including humans. The analysis of more than six hundred sequences allowed characterizing ubiquilin diversity in all the main eukaryotic groups. Many organisms (e. g. fungi, many animals) have single ubiquilin genes, but duplications in animal, plant, alveolate and excavate species are described. Seven different ubiquilins have been detected in vertebrates. Two of them, here called UBQLN5 and UBQLN6, had not been hitherto described. Significantly, marsupial and eutherian mammals have the most complex ubiquilin gene families, composed of up to 6 genes. This exceptional mammalian-specific expansion is the result of the recent emergence of four new genes, three of them (UBQLN3, UBQLN5 and UBQLNL) with precise testis-specific expression patterns that indicate roles in the postmeiotic stages of spermatogenesis. A gene with related features has independently arisen in species of the Drosophila genus. Positive selection acting on some mammalian ubiquilins has been detected.

Conclusions

The ubiquilin gene family is highly conserved in eukaryotes. The infrequent lineage-specific amplifications observed may be linked to the emergence of novel functions in particular tissues.

【 授权许可】

   
2014 Marín; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Vallen EA, Ho W, Winey M, Rose MD: Genetic interactions between CDC31 and KAR1, two genes required for duplication of the microtubule organizing center in Saccharomyces cerevisiae. Genetics 1994, 137:407-422.
• [2]Biggins S, Ivanovska I, Rose MD: Yeast ubiquitin-like genes are involved in duplication of the microtubule organizing center. J Cell Biol 1996, 133:1331-1346.
• [3]Funakoshi M, Geley S, Hunt T, Nishimoto T, Kobayashi H: Identification of XDRP1; a Xenopus protein related to yeast Dsk2p binds to the N-terminus of cyclin A and inhibits its degradation. EMBO J 1999, 18:5009-5018.
• [4]Wu AL, Wang J, Zheleznyak A, Brown EJ: Ubiquitin-related proteins regulate interaction of vimentin intermediate filaments with the plasma membrane. Mol Cell 1999, 4:619-625.
• [5]Kaye FJ, Modi S, Ivanovska I, Koonin EV, Thress K, Kubo A, Kornbluth S, Rose MD: A family of ubiquitin-like proteins binds the ATPase domain of Hsp70-like Stch. FEBS Lett. 2000, 467:348-355.
• [6]Mah AL, Perry G, Smith MA, Monteiro MJ: Identification of ubiquilin, a novel presenilin interactor that increases presenilin protein accumulation. J Cell Biol 2000, 151:847-862.
• [7]Kleijnen MF, Shih AH, Zhou P, Kumar S, Soccio RE, Kedersha NL, Gill G, Howley PM: The hPLIC proteins may provide a link between the ubiquitination machinery and the proteasome. Mol Cell. 2000, 6:409-419.
• [8]Conklin D, Holderman S, Whitmore TE, Maurer M, Feldhaus AL: Molecular cloning, chromosome mapping and characterization of UBQLN3 a testis-specific gene that contains an ubiquitin-like domain. Gene 2000, 249:91-98.
• [9]Davidson JD, Riley B, Burright EN, Duvick LA, Zoghbi HY, Orr HT: Identification and characterization of an ataxin-1-interacting protein: A1Up, a ubiquitin-like nuclear protein. Hum Mol Genet. 2000, 9:2305-2312.
• [10]Ozaki T, Hishiki T, Toyama Y, Yuasa S, Nakagawara A, Sakiyama S: Identification of a new cellular protein that can interact specifically with DAN. DNA Cell Biol 1997, 16:985-991.
• [11]Hanaoka E, Ozaki T, Ohira M, Nakamura Y, Suzuki M, Takahashi E, Moriya H, Nakagawara A, Sakiyama S: Molecular cloning and expression analysis of the human DA41 gene and its mapping to chromosome 9q21.2-q21.3. J Hum Genet. 2000, 45:188-191.
• [12]Matsuda M, Koide T, Yorihuzi T, Hosokawa N, Nagata K: Molecular cloning of a novel ubiquitin-like protein, UBIN, that binds to ER targeting signal sequences. Biochem Biophys Res Commun. 2001, 280:535-540.
• [13]Hayes MG, Pluzhnikov A, Miyake K, Sun Y, Ng MC, Roe CA, Below JE, Nicolae RI, Konkashbaev A, Bell GI, Cox NJ, Hanis CL: Identification of type 2 diabetes genes in Mexican Americans through genome-wide association studies. Diabetes 2007, 56:3033-3044.
• [14]Funakoshi M, Sasaki T, Nishimoto T, Kobayashi H: Budding yeast Dsk2p is a polyubiquitin-binding protein that can interact with the proteasome. Proc Natl Acad Sci U S A 2002, 99:745-750.
• [15]Wilkinson CR, Seeger M, Hartmann-Petersen R, Stone M, Wallace M, Semple C, Gordon C: Proteins containing the UBA domain are able to bind to multi-ubiquitin chains. Nat Cell Biol 2001, 3:939-943.
• [16]Elsasser S, Gali RR, Schwickart M, Larsen CN, Leggett DS, Müller B, Feng MT, Tübing F, Dittmar GA, Finley D: Proteasome subunit Rpn1 binds ubiquitin-like protein domains. Nat Cell Biol. 2002, 4:725-730.
• [17]Heessen S, Masucci MG, Dantuma NP: The UBA2 domain functions as an intrinsic stabilization signal that protects Rad23 from proteasomal degradation. Mol Cell 2005, 18:225-235.
• [18]Regan-Klapisz E, Sorokina I, Voortman J, de Keizer P, Roovers RC, Verheesen P, Urbé S, Fallon L, Fon EA, Verkleij A, Benmerah A, van Bergen en Henegouwen PM: Ubiquilin recruits Eps15 into ubiquitin-rich cytoplasmic aggregates via a UIM-UBL interaction. J Cell Sci 2005, 118:4437-4450.
• [19]Heir R, Ablasou C, Dumontier E, Elliott M, Fagotto-Kaufmann C, Bedford FK: The UBL domain of PLIC-1 regulates aggresome formation. EMBO Rep. 2006, 7:1252-1258.
• [20]Heinen C, Acs K, Hoogstraten D, Dantuma NP: C-terminal UBA domains protect ubiquitin receptors by preventing initiation of protein degradation. Nat Commun. 2011, 2:191.
• [21]Kang Y, Zhang N, Koepp DM, Walters KJ: Ubiquitin receptor proteins hHR23a and hPLIC2 interact. J Mol Biol. 2007, 365:1093-1101.
• [22]Di Fiore PP, Polo S, Hofmann K: When ubiquitin meets ubiquitin receptors: a signalling connection. Nat Rev Mol Cell Biol 2003, 4:491-497.
• [23]Elsasser S, Finley D: Delivery of ubiquitinated substrates to protein-unfolding machines. Nat Cell Biol 2005, 7:742-749.
• [24]Su V, Lau AF: Ubiquitin-like and ubiquitin-associated domain proteins: significance in proteasomal degradation. Cell Mol Life Sci 2009, 66:2819-2833.
• [25]Lee DY, Brown EJ: Ubiquilins in the crosstalk among proteolytic pathways. Biol Chem. 2012, 393:441-447.
• [26]Husnjak K, Dikic I: Ubiquitin-binding proteins: decoders of ubiquitin-mediated cellular functions. Annu Rev Biochem 2012, 81:291-322.
• [27]Haapasalo A, Viswanathan J, Bertram L, Soininen H, Tanzi RE, Hiltunen M: Emerging role of Alzheimer's disease-associated ubiquilin-1 in protein aggregation. Biochem Soc Trans. 2010, 38:150-155.
• [28]El Ayadi A, Stieren ES, Barral JM, Boehning D: Ubiquilin-1 and protein quality control in Alzheimer disease. Prion 2013, 7:164-169.
• [29]Massey LK, Mah AL, Ford DL, Miller J, Liang J, Doong H, Monteiro MJ: Overexpression of ubiquilin decreases ubiquitination and degradation of presenilin proteins. J Alzheimers Dis. 2004, 6:79-92.
• [30]Bertram L, Hiltunen M, Parkinson M, Ingelsson M, Lange C, Ramasamy K, Mullin K, Menon R, Sampson AJ, Hsiao MY, Elliott KJ, Velicelebi G, Moscarillo T, Hyman BT, Wagner SL, Becker KD, Blacker D, Tanzi RE: Family-based association between Alzheimer's disease and variants in UBQLN1. N Engl J Med 2005, 352:884-894.
• [31]Bensemain F, Chapuis J, Tian J, Shi J, Thaker U, Lendon C, Iwatsubo T, Amouyel P, Mann D, Lambert JC: Association study of the Ubiquilin gene with Alzheimer's disease. Neurobiol Dis. 2006, 22:691-693.
• [32]Brouwers N, Sleegers K, Engelborghs S, Bogaerts V, van Duijn CM, De Deyn PP, Van Broeckhoven C, Dermaut B: The UBQLN1 polymorphism, UBQ-8i, at 9q22 is not associated with Alzheimer's disease with onset before 70 years. Neurosci Lett. 2006, 392:72-74.
• [33]Kamboh MI, Minster RL, Feingold E, DeKosky ST: Genetic association of ubiquilin with Alzheimer's disease and related quantitative measures. Mol Psychiatry 2006, 11:273-279.
• [34]Slifer MA, Martin ER, Bronson PG, Browning-Large C, Doraiswamy PM, Welsh-Bohmer KA, Gilbert JR, Haines JL, Pericak-Vance MA: Lack of association between UBQLN1 and Alzheimer disease. Am J Med Genet B Neuropsychiatr Genet. 2006, 141B:208-213.
• [35]Smemo S, Nowotny P, Hinrichs AL, Kauwe JS, Cherny S, Erickson K, Myers AJ, Kaleem M, Marlowe L, Gibson AM, Hollingworth P, O'Donovan MC, Morris CM, Holmans P, Lovestone S, Morris JC, Thal L, Li Y, Grupe A, Hardy J, Owen MJ, Williams J, Goate A: Ubiquilin 1 polymorphisms are not associated with late-onset Alzheimer's disease. Ann Neurol. 2006, 59:21-26.
• [36]Arias-Vásquez A, de Lau L, Pardo L, Liu F, Feng BJ, Bertoli-Avella A, Isaacs A, Aulchenko Y, Hofman A, Oostra B, Breteler M, van Duijn C: Relationship of the Ubiquilin 1 gene with Alzheimer's and Parkinson's disease and cognitive function. Neurosci Lett. 2007, 424:1-5.
• [37]Golan MP, Melquist S, Safranow K, Styczyńska M, Słowik A, Kobryś M, Zekanowski C, Barcikowska M: Analysis of UBQLN1 variants in a Polish Alzheimer's disease patient: control series. Dement Geriatr Cogn Disord. 2008, 25:366-371.
• [38]Stieren ES, El Ayadi A, Xiao Y, Siller E, Landsverk ML, Oberhauser AF, Barral JM, Boehning D: Ubiquilin-1 is a molecular chaperone for the amyloid precursor protein. J Biol Chem. 2011, 286:35689-35698.
• [39]Viswanathan J, Haapasalo A, Böttcher C, Miettinen R, Kurkinen KM, Lu A, Thomas A, Maynard CJ, Romano D, Hyman BT, Berezovska O, Bertram L, Soininen H, Dantuma NP, Tanzi RE, Hiltunen M: Alzheimer's disease-associated ubiquilin-1 regulates presenilin-1 accumulation and aggresome formation. Traffic 2011, 12:330-348.
• [40]El Ayadi A, Stieren ES, Barral JM, Boehning D: Ubiquilin-1 regulates amyloid precursor protein maturation and degradation by stimulating K63-linked polyubiquitination of lysine 688. Proc Natl Acad Sci U S A 2012, 109:13416-13421.
• [41]Li A, Xie Z, Dong Y, McKay KM, McKee ML, Tanzi RE: Isolation and characterization of the Drosophila ubiquilin ortholog dUbqln: in vivo interaction with early-onset Alzheimer disease genes. Hum Mol Genet. 2007, 16:2626-2639.
• [42]Ganguly A, Feldman RM, Guo M: Ubiquilin antagonizes presenilin and promotes neurodegeneration in Drosophila. Hum Mol Genet 2008, 17:293-302.
• [43]Deng HX, Chen W, Hong ST, Boycott KM, Gorrie GH, Siddique N, Yang Y, Fecto F, Shi Y, Zhai H, Jiang H, Hirano M, Rampersaud E, Jansen GH, Donkervoort S, Bigio EH, Brooks BR, Ajroud K, Sufit RL, Haines JL, Mugnaini E, Pericak-Vance MA, Siddique T: Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature 2011, 477:211-215.
• [44]Daoud H, Suhail H, Szuto A, Camu W, Salachas F, Meininger V, Bouchard JP, Dupré N, Dion PA, Rouleau GA: UBQLN2 mutations are rare in French and French-Canadian amyotrophic lateral sclerosis. Neurobiol Aging 2012, 33:2230.e1-2230.e5.
• [45]Synofzik M, Maetzler W, Grehl T, Prudlo J, Vom Hagen JM, Haack T, Rebassoo P, Munz M, Schöls L, Biskup S: Screening in ALS and FTD patients reveals 3 novel UBQLN2 mutations outside the PXX domain and a pure FTD phenotype. Neurobiol Aging. 2012, 33:2949.e13-2949.e17.
• [46]Williams KL, Warraich ST, Yang S, Solski JA, Fernando R, Rouleau GA, Nicholson GA, Blair IP: UBQLN2/ubiquilin 2 mutation and pathology in familial amyotrophic lateral sclerosis. Neurobiol Aging. 2012, 33:2527.e3-2527.e10.
• [47]Kim SH, Shi Y, Hanson KA, Williams LM, Sakasai R, Bowler MJ, Tibbetts RS: Potentiation of amyotrophic lateral sclerosis (ALS)-associated TDP-43 aggregation by the proteasome-targeting factor, ubiquilin 1. J Biol Chem. 2009, 284:8083-8092.
• [48]Hanson KA, Kim SH, Wassarman DA, Tibbetts RS: Ubiquilin modifies TDP-43 toxicity in a Drosophila model of amyotrophic lateral sclerosis (ALS). J Biol Chem. 2010, 285:11068-11072.
• [49]Brettschneider J, Van Deerlin VM, Robinson JL, Kwong L, Lee EB, Ali YO, Safren N, Monteiro MJ, Toledo JB, Elman L, McCluskey L, Irwin DJ, Grossman M, Molina-Porcel L, Lee VM, Trojanowski JQ: Pattern of ubiquilin pathology in ALS and FTLD indicates presence of C9ORF72 hexanucleotide expansion. Acta Neuropathol. 2012, 123:825-839.
• [50]Riley BE, Xu Y, Zoghbi HY, Orr HT: The effects of the polyglutamine repeat protein ataxin-1 on the UbL-UBA protein A1Up. J Biol Chem 2004, 279:42290-42301.
• [51]Wang H, Lim PJ, Yin C, Rieckher M, Vogel BE, Monteiro MJ: Suppression of polyglutamine-induced toxicity in cell and animal models of Huntington's disease by ubiquilin. Hum Mol Genet 2006, 15:1025-1041.
• [52]Doi H, Mitsui K, Kurosawa M, Machida Y, Kuroiwa Y, Nukina N: Identification of ubiquitin-interacting proteins in purified polyglutamine aggregates. FEBS Letters 2004, 571:171-176.
• [53]Mori F, Tanji K, Odagiri S, Toyoshima Y, Yoshida M, Ikeda T, Sasaki H, Kakita A, Takahashi H, Wakabayashi K: Ubiquilin immunoreactivity in cytoplasmic and nuclear inclusions in synucleinopathies, polyglutamine diseases and intranuclear inclusión body disease. Acta Neuropathol. 2012, 124:149-151.
• [54]Rutherford NJ, Lewis J, Clippinger AK, Thomas MA, Adamson J, Cruz PE, Cannon A, Xu G, Golde TE, Shaw G, Borchelt DR, Giasson BI: Unbiased screen reveals ubiquilin-a and −2 highly associated with huntingtin inclusions. Brain Res. 2013, 1524:62-73.
• [55]González-Pérez P, Lu Y, Chian RJ, Sapp PC, Tanzi RE, Bertram L, McKenna-Yasek D, Gao FB, Brown RH Jr: Association of UBQLN1 mutation with Brown-Vialetto-Van Laere syndrome but not typical ALS. Neurobiol Dis. 2012, 48:391-398.
• [56]Lipinszki Z, Pál M, Nagy O, Deák P, Hunyadi-Gulyas E, Udvardy A: Overexpression of Dsk2/dUbqln results in severe developmental defects and lethality in Drosophila melanogaster that can be rescued by overexpression of the p54/Rpn10/S5a proteasomal subunit. FEBS J. 2011, 278:4833-4844.
• [57]Wu C, Macleod I, Su AI: BioGPS and MyGene.info: organizing online, gene-centric information. Nucleic Acids Res 2013, 41(Database issue):D561-D565.
• [58]Schultz N, Hamra FK, Garbers DL: A multitude of genes expressed solely in meiotic or postmeiotic spermatogenic cells offers a myriad of contraceptive targets. Proc Natl Acad Sci U S A 2003, 100:12201-12206.
• [59]Shima JE, McLean DJ, McCarrey JR, Griswold MD: The murine testicular transcriptome: characterizing gene expression in the testis during the progression of spermatogenesis. Biol Reprod 2004, 71:319-330.
• [60]Laiho A, Kotaja N, Gyenesei A, Sironen A: Transcriptome profiling of the murine testis during the first wave of spermatogenesis. PLoS One 2013, 8:e61558.
• [61]Bao J, Zhang J, Zheng H, Xu C, Yan W: UBQLN1 interacts with SPEM1 and participates in spermiogenesis. Mol Cell Endocrinol 2010, 327:89-97.
• [62]Chalmel F, Rolland AD, Niederhauser-Wiederkehr C, Chung SS, Demougin P, Gattiker A, Moore J, Patard JJ, Wolgemuth DJ, Jégou B, Primig M: The conserved transcriptome in human and rodent male gametogenesis. Proc Natl Acad Sci U S A. 2007, 104:8346-8351.
• [63]Yang Z: PAML 4: Phylogenetic analysis by maximum likelihood. Mol Biol Evol 2007, 24:1586-1591.
• [64]Fares MA, Bezemer D, Moya A, Marín I: Selection on coding regions determined Hox7 genes evolution. Mol. Biol. Evol 2003, 20:2104-2112.
• [65]Xu B, Yang Z: PAMLX: A graphical user interface for PAML. Mol. Biol Evol 2013, 30:2723-2724.
• [66]Marín I: Diversification and specialization of plant RBR ubiquitin ligases. PLoS One 2010, 5:e11579.
• [67]Marín I: Evolution of plant HECT ubiquitin ligases. PloS One 2013, 8:e68536.
• [68]N'Diaye EN, Kajihara KK, Hsieh I, Morisaki H, Debnath J, Brown EJ: PLIC proteins or ubiquilins regulate autophagy-dependent cell survival during nutrient starvation. EMBO Rep. 2009, 10:173-179.
• [69]Rothenberg C, Srinivasan D, Mah L, Kaushik S, Peterhoff CM, Ugolino J, Fang S, Cuervo AM, Nixon RA, Monteiro MJ: Ubiquilin functions in autophagy and is degraded by chaperone-mediated autophagy. Hum Mol Genet. 2010, 19:3219-3232.
• [70]Lee DY, Arnott D, Brown EJ: Ubiquilin4 is an adaptor protein that recruits Ubiquilin1 to the autophagy pathway. EMBO Rep 2013, 14:373-38.
• [71]Fatimababy AS, Lin YL, Usharani R, Radjacommare R, Wang HT, Tsai HL, Lee Y, Fu H: Cross-species divergence of the major recognition pathways of ubiquitylated substrates for ubiquitin/26S proteasome-mediated proteolysis. FEBS J. 2010, 277:796-816.
• [72]Zhang D, Raasi S, Fushman D: Affinity makes the difference: nonselective interaction of the UBA domain of Ubiquilin-1 with monomeric ubiquitin and polyubiquitin chains. J Mol Biol 2008, 377:162-180.
• [73]Sutovsky P: Ubiquitin-dependent proteolysis in mammalian spermatogenesis, fertilization, and sperm quality control: killing three birds with one stone. Microsc Res Tech 2003, 61:88-102.
• [74]Hermo L, Pelletier RM, Cyr DG, Smith CE: Surfing the wave, cycle, life history, and genes/proteins expressed by testicular germ cells. Part 4: intercellular bridges, mitochondria, nuclear envelope, apoptosis, ubiquitination, membrane/voltage-gated channels, methylation/acetylation, and transcription factors. Microsc Res Tech 2010, 73:364-408.
• [75]Hou CC, Yang WX: New insights to the ubiquitin-proteasome pathway (UPP) mechanism during spermatogenesis. Mol Biol Rep 2013, 40:3213-3230.
• [76]Hou X, Zhang W, Xiao Z, Gan H, Lin X, Hou X, Zhang W, Xiao Z, Gan H, Lin X, Liao S, Han C: Mining and characterization of ubiquitin E3 ligases expressed in the mouse testis. BMC Genomics 2012, 13:495. BioMed Central Full Text
• [77]Tanaka H, Baba T: Gene expression in spermiogenesis. Cell Mol Life Sci 2005, 62:344-354.
• [78]Hermo L, Pelletier RM, Cyr DG, Smith CE: Surfing the wave, cycle, life history, and genes/proteins expressed by testicular germ cells. Part 2: changes in spermatid organelles associated with development of spermatozoa. Microsc Res Tech 2010, 73:279-319.
• [79]Marín I: RBR ubiquitin ligases: diversification and streamlining in animal lineages. J Mol Evol 2009, 69:54-64.
• [80]Marín I: Origin and diversification of TRIM ubiquitin ligases. PLoS One 2012, 7:e50030.
• [81]Bedford JM: Puzzles of mammalian fertilization–and beyond. Int J Dev Biol. 2008, 52:415-426.
• [82]Nixon B, Ecroyd HW, Dacheux JL, Jones RC: Monotremes provide a key to understanding the evolutionary significance of epididymal sperm maturation. J Androl. 2011, 32:665-671.
• [83]Sun X, Kovacs T, Hu YJ, Yang WX: The role of actin and myosin during spermatogenesis. Mol Biol Rep 2011, 38:3993-4001.
• [84]Sperry AO: The dynamic cytoskeleton of the developing male germ cell. Biol Cell 2012, 104:297-305.
• [85]Katoh K, Toh H: Recent developments in the MAFFT multiple sequence alignment program. Brief Bioinform 2008, 9:286-298.
• [86]Nicholas KB, Nicholas HB jr: GeneDoc: a tool for editing and annotating multiple sequence alignments. 1997. Distributed by the author
• [87]Marín I: Ancient origin of animal U-box ubiquitin ligases. BMC Evol Biol 2010, 10:331. BioMed Central Full Text
• [88]Marín I: Animal HECT ubiquitin ligases: evolution and functional implications. BMC Evol Biol 2010, 10:56. BioMed Central Full Text
• [89]Tamura K, Peterson D, Peterson N, Stecher G, Nei M, Kumar S: MEGA5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. Mol Biol Evol 2011, 28:2731-2739.
• [90]Swofford DL: PAUP*. Phylogenetic Analysis Using Parsimony (*and Other Methods). Version 4. Sunderland, Massachusetts: Sinauer Associates; 2003.
• [91]Flicek P, Ahmed I, Amode MR, Barrell D, Beal K, Brent S, Carvalho-Silva D, Clapham P, Coates G, Fairley S, Fitzgerald S, Gil L, García-Girón C, Gordon L, Hourlier T, Hunt S, Juettemann T, Kähäri AK, Keenan S, Komorowska M, Kulesha E, Longden I, Maurel T, McLaren WM, Muffato M, Nag R, Overduin B, Pignatelli M, Pritchard B, Pritchard E, et al.: Ensembl. Nucleic Acids Res. 2013, 41(Database issue):D48-D55.
• [92]Zdobnov EM, Apweiler R: InterProScan - an integration platform for the signature-recognition methods in InterPro. Bioinformatics 2001, 17:847-848.