Abstract
CD45 of jawed vertebrates is a receptor-type protein tyrosine phosphatase regulating lymphocyte development and activation. To shed light on the evolution of the CD45 gene, the organization of its orthologue in the lamprey, a jawless vertebrate, was determined. Compared to its mammalian and fugu counterparts, the lamprey gene was found to be lacking several exons in the segment encoding the extracellular part of the protein. In consequence, this part contains only one instead of the two or three fibronectin type III domains typical of the mammalian molecules. The lamprey transcripts of the CD45 gene occur in several variants originating by alternative splicing, including some not observed previously in other vertebrates. Most remarkable of these are splice variants generated by the use of intra-exonic splicing signals and thus lacking one half, one third, or two thirds of an exon and yet apparently translated in the correct reading frame. The lamprey gene contains polymorphic sites not only in the segment encoding the extracellular portion but also in the segment specifying the cytoplasmic part of the molecule. Polymorphism is generated by both mutations and recombination. Some of the alleles may have persisted long enough to represent transspecies polymorphism presumably maintained by positive selection. Phylogenetic analysis suggests that ancestors of the CD45 gene may have existed before the divergence of coelomate from pseudocoelomate metazoans.
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Alonso A, Sasin J, Bottini N, Friedberg I, Friedberg I, Osterman A, Godzik A, Hunter T, Dixon J, Mustelin T (2004) Protein tyrosine phosphatases in the human genome. Cell 117:699–711
Anderson KL, Nelson SL, Perkin HB, Smith KA, Klemsz MJ, Torbett BE (2001) PU.1 is a lineage-specific regulator of tyrosine phosphatase CD45. J Biol Chem 276:7637–7642
Ballingall KT, Waibochi L, Holmes EC, Woelk CH, MacHugh ND, Lutje V, McKeever DJ (2001) The CD45 locus in cattle: allelic polymorphism and evidence for exceptional positive natural selection. Immunogenetics 52:276–283
Barclay AN, Jackson DI, Willis AC, Williams AF (1987) Lymphocyte specific heterogeneity in the rat leucocyte common antigen (T200) is due to differences in polypeptide sequences near the NH2-terminus. EMBO J 6:1259–1264
Bateman A, Coin L, Durbin R, Finn RD, Hollich V, Griffiths-Jones S, Khanna A, Marshall M, Moxon S, Sonnhammer EL, Studholme DJ, Yeats C, Eddy SR (2004) The Pfam protein families database. Nucleic Acids Res 32:I38–I41
Bork P, Doolittle RF (1993) Fibronectin type III modules in the receptor phosphatase CD45 and tapeworm antigens. Protein Sci 2:1185–1187
Díaz del Pozo E, Beverley PCL, Timon M (2000) Genomic structure and sequence of the leukocyte common antigen (CD45) from the pufferfish Fugu rubripes and comparison with its mammalian homologue. Immunogenetics 51:838–846
Felberg J, Johnson P (2000) Stable interdomain interaction within the cytoplasmic domain of CD45 increases enzyme stability. Biochem Biophys Res Commun 271:292–298
Filip LC, Mundy NI (2004) Rapid evolution by positive Darwinian selection in the extracellular domain of the abundant lymphocyte protein CD45 in primates. Mol Biol Evol 21:1504–1511
Fujiki K, Shin DH, Nakao M, Yano T (2000) Molecular cloning of carp (Cyprinus carpio) leucocyte cell-derived chemotaxin 2, glia maturation factor beta, CD45 and lysozyme C by use of suppression subtractive hybridization. Fish Shellfish Immunol 10:643–650
Hall LR, Streuli M, Schlossman SF, Saito H (1988) Complete exon–intron organization of the human leukocyte common antigen (CD45) gene. J Immunol 141:2781–2787
Hansen E, Lund O, Engelbrecht J, Bohr H, Nielsen JO, Hansen J-ES, Brunak S (1995) Prediction of O-glycosylation of mammalian proteins: specificity patterns of UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase. Biochem J 308:801–813
Hansen E, Lund O, Rapacki K, Brunak S (1997) O-glycbase version 2.0-A revised database of O-glycosylated proteins. Nucleic Acids Res 25:278–282
Hansen E, Lund O, Tolstrup N, Gooley AA, Williams KL, Brunak S (1998) NetOglyc: prediction of mucin type O-glycosylation sites based on sequence context and surface accessibility. Glycoconj J 15:115–130
Hermiston ML, Xu Z, Weiss A (2003) CD45: a critical regulator of signaling thresholds in immune cells. Annu Rev Immunol 21:107–137
Irie-Sasaki J, Sasaki T, Matsumoto W, Opavsky A, Cheng M, Welstead G, Griffiths E, Krawczyk C, Richardson CD, Aitken K, Iscove N, Koretzky G, Johnson P, Liu P, Rothstein DM, Penninger JM (2001) CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling. Nature 409:349–354
Johnson NA, Meyer CM, Pingel JT, Thomas ML (1989) Sequence conservation in potential regulatory regions of the mouse and human-leukocyte common antigen gene. J Biol Chem 264:6220–6229
Julenius K, Molgaard A, Gupta R, Brunak S (2005) Prediction, conservation analysis and structural characterization of mammalian mucin-type O-glycosylation sites. Glycobiology 15:152–164
Justement LB (1997) The role of CD45 in signal transduction. Adv Immunol 66:1–65
Klein J (1987) Origin of major histocompatibility complex polymorphism: the trans-species hypothesis. Hum Immunol 19:155–162
Kountikov E, Wilson M, Quiniou S, Miller N, Clem W, Bengten E (2005) Genomic organization of the channel catfish CD45 functional gene and CD45 pseudogenes. Immunogenetics 57:374–383
Kuroda N, Uinuk-ool TS, Sato A, Samonte IE, Figueroa F, Mayer WE, Klein J (2003) Identification of chemokines and a chemokine receptor in cichlid fish, shark, and lamprey. Immunogenetics 54:884–895
Leahy DJ, Hendrickson WA, Aukhil I, Erickson HP (1992) Structure of a fibronectin type III domain from tenascin phased by MAD analysis of the selenomethionyl protein. Science 258:987–991
Letunic I, Copley RR, Schmidt S, Ciccarelli FD, Doerks T, Schultz J, Ponting CP, Bork P (2004) Smart 4.0: towards genomic data integration. Nucleic Acids Res 32:I42–I44
Mayer WE, Uinuk-Ool T, Tichy H, Gartland LA, Klein J, Cooper MD (2002) Isolation and characterization of lymphocyte-like cells from a lamprey. Proc Natl Acad Sci U S A 99:14350–14355
Montoya GE, Vernot JP, Patarroyo ME (2004) Comparative analysis of CD45 proteins in primate context: owl monkeys vs humans. Tissue Antigens 64:165–172
Mustelin T, Rahmouni S, Bottini N, Alonso A (2003) Role of protein tyrosine phospatases in T cell activation. Immunol Rev 191:139–147
Nagata T, Suzuki T, Ohta Y, Flajnik MF, Kasahara M (2002) The leukocyte common antigen (CD45) of the Pacific hagfish, Eptatretus stoutii: implications for the primordial function of CD45. Immunogenetics 54:286–291
Nam HJ, Poy F, Krueger NX, Saito H, Frederick CA (1999) Crystal structure of the tandem phosphatase domains of RPTP LAR. Cell 97:449–457
Nam HJ, Poy F, Saito H, Frederick CA (2005) Structural basis for the function and regulation of the receptor protein tyrosine phosphatase CD45. J Exp Med 201:441–452
Nielsen H, Krogh A (1998) Prediction of signal peptides and signal anchors by a hidden Markov model. Proceedings of the sixth international conference on intelligent systems for Molecular Biology (ISMB 6). AAAI Press, Menlo Park, CA, p 122
Nielsen H, Engelbrecht J, Brunak S, von Heijne G (1997) Identification of prokaryotic and eukaryotic signal peptides and prediction of their cleavage sites. Protein Eng 10:1–6
Okumura M, Matthews RJ, Robb B, Litman GW, Bork P, Thomas ML (1996) Comparison of CD45 extracellular domain sequences from divergent vertebrate species suggests the conservation of three fibronectin type III domains. J Immunol 157:1569–1575
Pedersen G, Nielsen H (1997) Neural network prediction of translation initiation sites in eukaryotes: perspectives for EST and genome analysis. ISMB 5:226–233
Pils B, Schultz J (2004) Evolution of the multifunctional protein tyrosine phosphatase family. Mol Biol Evol 21:625–631
Powell LD, Sgroi D, Sjoberg ER, Stamenkovic I, Varki A (1993) Natural ligands of the B cell adhesion molecule CD22 beta carry N-linked oligosaccharides with alpha-2,6-linked sialic acids that are required for recognition. J Biol Chem 268:7019–7027
Saga Y, Tung JS, Shen FW, Boyse EA (1986) Sequences of Ly-5 cDNA: isoform-related diversity of Ly-5 mRNA. Proc Natl Acad Sci U S A 83:6940–6944
Sato T, Furukawa K, Autero M, Gahmberg CG, Kobata A (1993) Structural study of the sugar chains of human leukocyte common antigen CD45. Biochemistry 32:12694–12704
Schug J, Overton GC (1997) Technical Report CBIL-TR-1997-1001-v0.0. Computational Biology and Informatics Laboratory, School of Medicine, University of Pennsylvania, Pennsylvania
Shintani S, Terzic J, Sato A, Saraga-Babic M, O'hUigin C, Tichy H, Klein J (2000) Do lampreys have lymphocytes? The Spi evidence. Proc Natl Acad Sci U S A 97:7417–7422
Symons A, Willis AC, Barclay AN (1999) Domain organization of the extracellular region of CD45. Protein Eng 12:885–892
Thomas ML (1989) The leukocyte common antigen family. Annu Rev Immunol 7:339–369
Trowbridge IS, Thomas ML (1994) CD45: an emerging role as a protein tyrosine phosphatase required for lymphocyte activation and development. Annu Rev Immunol 12:85–116
Uemura K, Yokota Y, Kozutsumi Y, Kawasaki T (1996) A unique CD45 glycoform recognized by the serum mannan-binding protein in immature thymocytes. J Biol Chem 271:4581–4584
Uinuk-Ool T, Mayer WE, Sato A, Dongak R, Cooper MD, Klein J (2002) Lamprey lymphocyte-like cells express homologs of genes involved in immunologically relevant activities of mammalian lymphocytes. Proc Natl Acad Sci U S A 99:14356–14361
Virts E, Barritt D, Raschke WC (1998) Expression of the CD45 isoforms lacking exons 7, 8 and 10. Mol Immunol 35:167–176
Acknowledgements
We thank Professor Masatoshi Nei for his support of our work and Kathleen Seasholtz for editorial assistance. JK thanks Jongmin Nam for his unsparing help in dealing with HAL's caprices. NN was supported by grant GM20293 from the National Institutes of Health to MN.
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Uinuk-ool, T., Nikolaidis, N., Sato, A. et al. Organization, alternative splicing, polymorphism, and phylogenetic position of lamprey CD45 gene. Immunogenetics 57, 607–617 (2005). https://doi.org/10.1007/s00251-005-0019-8
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DOI: https://doi.org/10.1007/s00251-005-0019-8