Abstract
It was shown previously that, as differentiated from canonical proteases, abzymes against myelin basic protein (MBP) from blood of patients with multiple sclerosis and systemic lupus erythematosus effectively cleaved only MBP, while antibodies (ABs) against integrase (IN) from blood of HIV-infected patients specifically hydrolyzed only IN. In this work, all sites of effective hydrolysis by anti-IN antibodies (IgG and IgM) of 25-mer oligopeptide (OP25) corresponding to MBP were identified using reversed-phase and thin-layer chromatographies and MALDI mass spectrometry. It was found that amino acid sequences of OP25 and other oligopeptides hydrolyzed by anti-MBP abzymes were partially homologous to some fragments of the full sequence of IN. Sequences of IN oligopeptides cleavable by anti-IN abzymes were homologous to some fragments of MBP, but anti-MBP abzymes could not effectively hydrolyze OPs corresponding to IN. The common features of the cleavage sites of OP25 and other oligopeptides hydrolyzed by anti-MBP and anti-IN abzymes were revealed. The literature data on hydrolysis of specific and nonspecific proteins and oligopeptides by abzymes against different protein antigens were analyzed. Overall, the literature data suggest that short OPs, including OP25, mainly interact with light chains of polyclonal ABs, which had lower affinity and specificity to the substrate than intact ABs. However, it seems that anti-IN ABs are the only one example of abzymes capable of hydrolyzing various oligopeptides with high efficiency (within some hours but not days). Possible reasons for the efficient hydrolysis of foreign oligopeptides by anti-IN abzymes from HIV-infected patients are discussed.
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Abbreviations
- AB:
-
antibody
- FM:
-
final reaction mixture
- HIV:
-
human immunodeficiency virus
- HSA:
-
human serum albumin
- IAS:
-
immunogenic amino acid sequence
- IgGmix and IgMmix :
-
mixtures of individual antibodies from blood of HIV-infected patients
- IN:
-
HIV integrase
- MBP:
-
myelin basic protein
- MCA:
-
4-methylcoumaryl-7-amine
- MS:
-
multiple sclerosis
- OP:
-
oligopeptide
- RPC:
-
reverse-phase chromatography
- SLE:
-
systemic lupus erythematosus
- X:
-
fluorescent residue 6-O-(carboxymethyl)fluorescein ethyl ester
References
Keinan, E. (ed.) (2005) Catalytic Antibodies, Wiley-VCH Verlag GmbH and Co. KgaA, Weinheim, Germany.
Nevinsky, G. A., and Buneva, V. N. (2002) Human catalytic RNA- and DNA-hydrolyzing antibodies, J. Immunol. Methods, 269, 235–249.
Nevinsky, G. A., and Buneva, V. N. (2005) Natural catalytic antibodies — abzymes, in Catalytic Antibodies (Keinan, E., ed.) VCH-Wiley, Weinheim, Germany, pp. 503–567.
Nevinsky, G. A. (2010) Natural catalytic antibodies in norm and in autoimmune diseases, in Autoimmune Diseases: Symptoms, Diagnosis and Treatment (Brenner, K. J., ed.) Nova Science Publishers, Inc., USA.
Nevinsky, G. A. (2011) Natural catalytic antibodies in norm and in HIV-infected patients, in Understanding HIV/AIDS Management and Care — Pandemic Approaches the 21st Century (Kasenga, F. H., ed.) InTech, Rijeka, Croatia, pp. 151–192.
Nevinsky, G. A., and Buneva, V. N. (2012) Autoantibodies and natural catalytic antibodies in health, multiple sclerosis, and some other diseases, Adv. Neuroimmune Biol., 3, 157–182.
Fauci, A. S., Braunwald, E., Kasper, D. L., Hauser, S. L., Longo, D. L., and Jameson, J. L. (2008) Harrison’s Principles of Internal Medicine, 7th Edn., McGraw-Hill Professional, New York.
Katz, A. R., and Skalka, A. M. (1994) HIV-1 integrase: structural organization, conformational changes, and catalysis, Ann. Rev. Biochem., 63, 133–173.
Litvak, S. (1996) Retroviral reverse transcriptases, in Molecular Biology Intelligency Unit Series (Landes, R., ed.) Chapman and Hall/Springer Verlag, Heidelberg.
Skalka, A. M., and Goff, S. P. (1993) Reverse Transcriptase, Cold Spring Harbor Laboratory Press, New York.
Asante-Appiah, E., and Skalka, A. M. (1999) HIV-1 integrase: structural organization, conformational changes, and catalysis, Adv. Virus Res., 52, 351–369.
Verkoczy, L., and Diaz, M. (2014) Autoreactivity in HIV-1 broadly neutralizing antibodies: implications for their function and induction by vaccination, Curr. Opin. HIV AIDS, 9, 224–234.
Zandman-Goddard, G., and Shoenfeld, Y. (2002) HIV and autoimmunity, Autoimmun. Rev., 1, 329–337.
Gololobov, G. V., Mikhalap, S. V., Starov, A. V., Kolesnikov, A. F., and Gabibov, A. G. (1994) DNA-protein complexes. Natural targets for DNA-hydrolyzing antibodies, Appl. Biochem. Biotechnol., 47, 305–314.
Odintsova, E. S., Kharitonova, M. A., Baranovskii, A. G., Sizyakina, L. P., Buneva, V. N., and Nevinsky, G. A. (2006) DNA-hydrolyzing IgG antibodies from the blood of patients with acquired immune deficiency syndrome, Mol. Biol., 40, 857–864.
Odintsova, E. S., Kharitonova, M. A., Baranovskii, A. G., Sizyakina, L. P., Buneva, V. N., and Nevinsky, G. A. (2006) Proteolytic activity of IgG antibodies from blood of acquired immunodeficiency syndrome patients, Biochemistry (Moscow), 71, 251–261.
Baranova, S. V., Buneva, V. N., Kharitonova, M. A., Sizyakina, L. P., Calmels, C., Parissi, V., Andreola, M. L., Buneva, V. N., Zakharova, O. D., and Nevinsky, G. A. (2010) HIV-1 integrase-hydrolyzing IgM antibodies from sera of HIV-infected patients, Int. Immunol., 22, 671–680.
Baranova, S. V., Buneva, V. N., Kharitonova, M. A., Sizyakina, L. P., Calmels, C., Andreola, M. L., Parissi, V., and Nevinsky, G. A. (2009) HIV-1 integrase-hydrolyzing antibodies from sera of HIV-infected patients, Biochimie, 91, 1081–1086.
Odintsova, E. S., Baranova, S. V., Dmitrenok, P. S., Rasskazov, V. A., Calmels, C., Parissi, V., Andreola, M. L., Buneva, V. N., Zakharova, O. D., and Nevinsky, G. A. (2011) Antibodies to HIV integrase catalyze site-specific degradation of their antigen, Int. Immunol., 23, 601–612.
Odintsova, E. S., Dmitrenok, P. S., Buneva, V. N., and Nevinsky, G. A. (2013) Specific anti-integrase abzymes from HIV-infected patients: a comparison of the cleavage sites of intact globular HIV integrase and two 20-mer oligopeptides corresponding to its antigenic determinants, J. Mol. Recognit., 26, 121–135.
O’Connor, K. C., Bar-Or, A., and Hafler, D. A. (2001) Neuroimmunology of multiple sclerosis, J. Clin. Immunol., 21, 81–92.
Archelos, J. J., Storch, M. K., and Hartung, H. P. (2000) The role of B cells and autoantibodies in multiple sclerosis, Ann. Neurol., 47, 694–706.
Hemmer, B., Archelos, J. J., and Hartung, H. P. (2002) New concepts in the immunopathogenesis of multiple sclerosis, Nat. Rev. Neurosci., 3, 291–301.
Polosukhina, D. I., Kanyshkova, T. G., Doronin, B. M., Tyshkevich, O. B., Buneva, V. N., Boiko, A. N., Gusev, E. I., Favorova, O. O., and Nevinsky, G. A. (2004) Hydrolysis of myelin basic protein by polyclonal catalytic IgGs from the sera of patients with multiple sclerosis, J. Cell. Mol. Med., 8, 359–368.
Polosukhina, D. I., Buneva, V. N., Doronin, B. M., Tyshkevich, O. B., Boiko, A. N., Gusev, E. I., Favorova, O. O., and Nevinsky, G. A. (2005) Hydrolysis of myelin basic protein by IgM and IgA antibodies from the sera of patients with multiple sclerosis, Med. Sci. Monit., 11, BR266–BR272.
Polosukhina, D. I., Kanyshkova, T. G., Doronin, B. M., Tyshkevich, O. B., Buneva, V. N., Boiko, A. N., Gusev, E. I., Nevinsky, G. A., and Favorova, O. O. (2006) Metal-dependent hydrolysis of myelin basic protein by IgGs from the sera of patients with multiple sclerosis, Immunol. Lett., 103, 75–81.
Ponomarenko, N. A., Durova, O. M., Vorobiev, I. I., Belogurov, A. A., Kurkova, I. N., Petrenko, A. G., Telegin, G. B., Suchkov, S. V., Kiselev, S. L., Lagarkova, M. A., Govorun, V. M., Serebryakova, M. V., Avalle, B., Tornatore, P., Karavanov, A., Morse, H. C. 3rd, Thomas, D., Friboulet, A., and Gabibov, A. G. (2006) Autoantibodies to myelin basic protein catalyze site-specific degradation of their antigen, Proc. Natl. Acad. Sci. USA, 103, 281–286.
Hhachn, B. Ch. (1996) Systemic lupus erythematosus, in Internal Diseases (Braunvald, E. E., Isselbakher, K. D., Petersdorf, R. G., Wilson, D. D., Martin. D. B., and Fauchi, A. S., eds.) [Russian translation], Meditsina, Moscow.
Bezuglova, A. M., Konenkova, L. P., Doronin, B. M., Buneva, V. N., and Nevinsky, G. A. (2011) Affinity and catalytic heterogeneity and metal-dependence of polyclonal myelin basic protein-hydrolyzing IgGs from sera of patients with systemic lupus erythematosus, J. Mol. Recognit., 24, 960–974.
Bezuglova, A. M., Dmitrenok, P. S., Konenkova, L. P., Buneva, V. N., and Nevinsky, G. A. (2012) Multiple sites of the cleavage of 17- and 19-mer encephalitogenic oligopeptides corresponding to human myelin basic protein (MBP) by specific anti-MBP antibodies from patients with systemic lupus erythematosus, Peptides, 37, 69–78.
Timofeeva, A. M., Dmitrenok, P. S., Konenkova, L. P., Buneva, V. N., and Nevinsky G. A. (2013) Multiple sites of the cleavage of 21- and 25-mer encephalitogenic oligopeptides corresponding to human myelin basic protein (MBP) by specific anti-MBP antibodies from patients with systemic lupus erythematosus, PLoS One, 8, e51600.
Bezuglova, A. M., Konenkova, L. P., Buneva, V. N., and Nevinsky, G. A. (2012) IgGs containing light chains of the λ- and κ-type and of all subclasses (IgG1-IgG4) from the sera of patients with systemic lupus erythematosus hydrolyze myelin basic protein, Int. Immunol., 12, 759–770.
Odintsova, E. S., Dmitrenok, P. S., Timofeeva, A. M., Buneva, V. N., and Nevinsky, G. A. (2014) Why specific anti-integrase antibodies from HIV-infected patients can efficiently hydrolyze 21-mer oligopeptide corresponding to antigenic determinant of human myelin basic protein, J. Mol. Recognit., 27, 32–45.
Odintsova, E. S., Baranova, S. V., Dmitrenok, P. S., Calmels, C., Parissi, V., Andreola, M. L., Buneva, V. N., and Nevinsky, G. A. (2012) Anti-integrase abzymes from the sera of HIV-infected patients specifically hydrolyze integrase but nonspecifically cleave short oligopeptides, J. Mol. Recognit., 25, 193–207.
Caumont, A., Jamieson, G., de Soultrait, V., Parissi, V., Fournier, M., Zakharova, O. D., Bayandin, R., Litvak, S., Tarrago-Litvak, L., and Nevinsky, G. A. (1999) High affinity interaction of HIV-1 integrase with specific and nonspecific single-stranded short oligonucleotides, FEBS Lett., 455, 154–158.
Huang, X., and Miller, W. (1991) Local alignment of two-base encoded DNA sequence, Adv. Appl. Math., 12, 337–357.
Paul, S., Li, L., Kalaga, R., O’Dell, J., Dannenbring, R. E., Swindells, S., Hinrichs, S., Cauturegli, P., and Rose, N. R. (1997) Characterization of thyroglobulin-directed and polyreactive catalytic antibodies in autoimmune disease, J. Immunol., 159, 1530–1536.
Kalaga, R., Li, L., O’Dell, J. R., and Paul, S. (1995) Unexpected presence of polyreactive catalytic antibodies in IgG from unimmunized donors and decreased levels in rheumatoid arthritis, J. Immunol., 155, 2695–2702.
Paul, S., Li, L., Kalaga, R., Wilkins-Stevens, P., Stevens, F. J., and Solomon, A. (1995) Natural catalytic antibodies: peptide-hydrolyzing activities of Bence-Jones proteins and VL fragment, J. Biol. Chem., 270, 15257–15261.
Yi, J., Arthur, J. W., Dunbrack, R. L., and Skalka, A. M. (2000) An inhibitory monoclonal antibody binds at the turn of the helix-turn-helix motif in the N-terminal domain of HIV-1 integrase, J. Biol. Chem., 275, 38739–38748.
Bizub-Bender, D., Kulkosky, J., and Skalka, A. M. (1994) Monoclonal antibodies against HIV type 1 integrase: clues to molecular structure, AIDS Res. Hum. Retroviruses, 10, 1105–1115.
Nilsen, B. M., Haugan, I. R., Berg, K., Olsen, L., Brown, P. O., and Helland, D. E. (1996) Monoclonal antibodies against human immunodeficiency virus type 1 integrase: epitope mapping and differential effects on integrase activities in vitro, J. Virol., 70, 1580–1587.
Baranovskii, A. G., Buneva, V. N., Doronin, B. M., and Nevinsky, G. A. (2008) Immunoglobulins from blood of patients with multiple sclerosis are catalytically heterogeneous nucleases, Ros. Immunol. Zh., 2, 405–419.
Andrievskaya, O. A., Buneva, V. N., Baranovskii, A. G., Gal’vita, A. V., Benzo, E. S., Naumov, V. A., and Nevinsky, G. A. (2002) Catalytic diversity of polyclonal RNA-hydrolyzing IgG antibodies from the sera of patients with systemic lupus erythematosus, Immunol. Lett., 81, 191–198.
Galvita, A. V., Baranovskii, A. G., Kuznetsova, I. A., Vinshu, N. V., Galenok, V. A., Buneva, V. N., and Nevinsky, G. A. (2007) Peculiarities of DNA hydrolysis by antibodies from blood of patients with pancreatic diabetes, Rus. J. Immunol., 1, 116–131.
Parkhomenko, T. A., Buneva, V. N., Tyshkevich, O. B., Generalov, I. I., Doronin, B. M., and Nevinsky, G. A. (2010) DNA-hydrolyzing activity of IgG antibodies from the sera of patients with tick-borne encephalitis, Biochimie, 92, 545–554.
Parkhomenko, T. A., Odintsova, E. S., Buneva, V. N., Kunder, E. V., Zhyltsov, I. V., Senkovich, S. A., Generalov, I. I., and Nevinsky, G. A. (2009) DNA-hydrolyzing activity of IgG antibodies from the sera of patients with diseases caused by different bacterial infections, J. Cell. Mol. Med., 13, 2875–2887.
Kanyshkova, T. G., Semenov, D. V., Buneva, V. N., and Nevinsky, G. A. (1999) Human milk lactoferrin binds two molecules of DNA with different affinities, FEBS Lett., 451, 235–237.
Kuznetsova, I. A., Orlovskaya, I. A., Buneva, V. N., and Nevinsky, G. A. (2007) Activation of DNA-hydrolyzing antibodies from the sera of autoimmune-prone MRLlpr/lpr mice by different metal ions, Biochim. Biophys. Acta, 1774, 884–896.
Andryushkova, A. A., Kuznetsova, I. A., Orlovskaya, I. A., Buneva, V. N., and Nevinsky, G. A. (2006) Antibodies with amylase activity from the sera of autoimmune-prone MRL/MpJ-lpr mice, FEBS Lett., 580, 5089–5095.
Andryushkova, A. A., Kuznetsova, I. A., Orlovskaya, I. A., Buneva, V. N., and Nevinsky, G. A. (2009) Nucleotidehydrolyzing antibodies from the sera of autoimmune-prone MRL-lpr/lpr mice, Int. Immunol., 21, 935–945.
Botvinovskaya, A. V., Kostrikina, I. A., Buneva, V. N., and Nevinsky, G. A. (2013) Systemic lupus erythematosus: molecular cloning of several recombinant DNase monoclonal kappa light chains with different catalytic properties, J. Mol. Recognit., 26, 450–460.
Kostrikina, I. A., Buneva, V. N., and Nevinsky, G. A. (2014) Systemic lupus erythematosus: molecular cloning of fourteen recombinant DNase monoclonal kappa light chains with different catalytic properties, Biochim. Biophys. Acta, 1840, 1725–1737.
Sun, M., Gao, Q. S., Kirnarskiy, L., Rees, A., and Paul, S. (1997) Cleavage specificity of a proteolytic antibody light chain and effects of the heavy chain variable domain, J. Mol. Biol., 271, 374–385.
Thiagarajan, P., Dannenbring, R., Matsuura, K., Tramontano, A., Gololobov, G., and Paul, S. (2000) Monoclonal antibody light chain with prothrombinase activity, Biochemistry, 39, 6459–6465.
Rangan, S. K., Liu, R., Brune, D., Plaque, S., Paul, S., and Sierks, M. R. (2003) Degradation of beta-amyloid by proteolytic antibody light chains, Biochemistry, 42, 14328–14334.
Mitsuda, Y., Hifimi, E., Tsuruhata, R., Fujinami, H., Yamamoto, N., and Uda, T. (2004) Catalytic antibody light chain capable of cleaving a chemokine receptor CCR-5 peptide with a high reaction rate constant, Biotechnol. Bioeng., 86, 217–225.
Nidhiyama, Y., Karle, S., Planque, S., Taguchi, H., and Paul, S. (2007) Antibodies to the superantigenic site of HIV-1 gp120, hydrolytic and binding activities of the light chain subunit, Mol. Immunol., 44, 2707–2718.
Taguchi, H., Keck, Z., Foung, S. K., Paul, S., and Nishiyama, Y. (2004) Antibody light chain-catalyzed hydrolysis of a hepatitis C virus peptide, Bioorg. Med. Chem. Lett., 14, 4529–4532.
Hifumi, E., Morihara, F., Hatiuchi, K., Okuda, T., Nishisono, A., and Uda, T. (2008) Catalytic features and eradication ability of antibody light-chain UA15-L against Helicobacter pylori, J. Biol. Chem., 283, 899–907.
Li, L., Paul, S., Tyutyulkova, S., Kazatchkine, M. D., and Kavery, S. (1995) Catalytic activity of anti-thyroglobulin antibodies, J. Immunol., 154, 3328–3332.
Gao, Q. S., Sun, M., Tyutyulkova, S., Webster, D., Rees, A., Tramontano, A., Massey, R. J., and Paul, S. (1994) Molecular cloning of a proteolytic antibody light chain, J. Biol. Chem., 269, 32389–32393.
Fersht, A. (1985) Enzyme Structure and Mechanism, 2nd Edn., W. H. Freeman, Co., N. Y.
Nevinsky, G. A. (2003) in Protein Structures: Kaleidoscope of Structural Properties and Functions (Uversky, V. N., ed.) Research Signpost, Kerala, pp. 133–222.
Paul, S., Volle, D. J., Beach, C. M., Johnson, D. R., Powell, M. J., and Massey, R. J. (1989) Catalytic hydrolysis of vasoactive intestinal peptide by human autoantibody, Science, 244, 1158–1162.
Lacroix-Desmazes, S., Moreau, A., Sooryanarayana, Bonnemain, C., Stieltjes, N., Pashov, A., Sultan, Y., Hoebeke, J., Kazatchkine, M. D., and Kaveri, S. V. (1999) Catalytic activity of antibodies against factor VIII in patients with hemophilia A, Nat. Med., 5, 1044–1047.
Odintsova, E. S., Buneva, V. N., and Nevinsky, G. A. (2005) Casein-hydrolyzing activity of sIgA antibodies from human milk, J. Mol. Recognit., 18, 413–421.
Paul, S., Karle, S., Planque, S., Taguchi, H., Salas, M., Nishiyama, Y., Handy, B., Hunter, R., Edmundson, A., and Hanson, C. (2004) Naturally occurring proteolytic antibodies: selective immunoglobulin M-catalyzed hydrolysis of HIV gp120, J. Biol. Chem., 279, 39611–39619.
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Original Russian Text © E. S. Odintsova, P. S. Dmitrenok, S. V. Baranova, A. M. Timofeeva, V. N. Buneva, G. A. Nevinsky, 2015, published in Biokhimiya, 2015, Vol. 80, No. 2, pp. 224–248.
Originally published in Biochemistry (Moscow) On-Line Papers in Press, as Manuscript BM14-187, January 25, 2015.
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Odintsova, E.S., Dmitrenok, P.S., Baranova, S.V. et al. Features of hydrolysis of specific and nonspecific globular proteins and oligopeptides by antibodies against viral integrase from blood of HIV-infected patients. Biochemistry Moscow 80, 180–201 (2015). https://doi.org/10.1134/S0006297915020054
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DOI: https://doi.org/10.1134/S0006297915020054