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IGFBP-4 Proteolysis by PAPP-A in a Primary Culture of Rat Neonatal Cardiomyocytes under Normal and Hypertrophic Conditions

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Abstract

Cardiovascular diseases (CVD) are among the leading causes of death and disability worldwide. Pregnancy-associated plasma protein-A (PAPP-A) is a matrix metalloprotease localized on the cell surface. One of the substrates that PAPP-A cleaves is the insulin-like growth factor binding protein-4 (IGFBP-4), a member of the family of proteins that bind insulin-like growth factor (IGF). Proteolysis of IGFBP-4 by PAPP-A occurs at a specific site resulting in formation of two proteolytic fragments – N-terminal IGFBP-4 (NT-IGFBP-4) and C-terminal IGFBP-4 (CT-IGFBP-4), and leads to the release of IGF activating various cellular processes including migration, proliferation, and cell growth. Increased levels of the proteolytic IGFBP-4 fragments correlate with the development of CVD complications and increased risk of death in patients with the coronary heart disease, acute coronary syndrome, and heart failure. However, there is no direct evidence that PAPP-A specifically cleaves IGFBP-4 in the cardiac tissue under normal and pathological conditions. In the present study, using a primary culture of rat neonatal cardiomyocytes as a model, we have demonstrated that: 1) proteolysis of IGFBP-4 by PAPP-A occurs in the conditioned medium of cardiomyocytes, 2) PAPP-A-specific IGFBP-4 proteolysis is increased when cardiomyocytes are transformed to a hypertrophic state. Thus, it can be assumed that the enhancement of IGFBP-4 cleavage by PAPP-A and hypertrophic changes in cardiomyocytes accompanying CVD are interrelated, and PAPP-A appears to be one of the activators of the IGF-dependent processes in normal and hypertrophic-state cardiomyocytes.

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Abbreviations

ACS:

acute coronary syndrome

BNP:

natriuretic peptide type B

CT-IGFBP-4:

C-terminal proteolytic IGFBP-4 fragment

CVD:

cardiovascular deceases

DAPI:

4′,6-diamidino-2-phenylindole

dPAPP-A:

PAPP-A, dimeric form

HF:

heart failure

IGF:

insulin-like growth factor

IGFBP-2-5:

insulin growth factor binding protein 2-5

NT-IGFBP-4:

N-terminal proteolytic IGFBP-4 fragment

PAPP-A:

pregnancy associated plasma protein A

References

  1. Bhatnagar, P., Wickramasinghe, K., Williams, J., Rayner, M., and Townsend, N. (2015) The epidemiology of cardiovascular disease in the UK 2014, Heart, 101, 1182-1189, https://doi.org/10.1136/heartjnl-2015-307516.

    Article  CAS  PubMed  Google Scholar 

  2. Rame, J. E., and Dries, D. L. (2007) Heart failure and cardiac hypertrophy, Curr. Treat. Options Cardiovasc. Med., 9, 289-301, https://doi.org/10.1007/s11936-007-0024-3.

    Article  PubMed  Google Scholar 

  3. Shimizu, I., and Minamino, T. (2016) Physiological and pathological cardiac hypertrophy, J. Mol. Cell Cardiol., 97, 245-262, https://doi.org/10.1016/j.yjmcc.2016.06.001.

    Article  CAS  PubMed  Google Scholar 

  4. Hjortebjerg, R. (2018) IGFBP-4 and PAPP-A in normal physiology and disease, Growth Horm. IGF Res., 41, 7-22, https://doi.org/10.1016/j.ghir.2018.05.002.

    Article  CAS  PubMed  Google Scholar 

  5. Lin, T. M., Halbert, S. P., and Spellacy, W. N. (1974) Measurement of pregnancy-associated plasma proteins during human gestation, J. Clin. Invest., 54, 576-582, https://doi.org/10.1172/JCI107794.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Overgaard, M. T., Sorensen, E. S., Stachowiak, D., Boldt, H. B., Kristensen, L., Sottrup-Jensen, L., and Oxvig, C. (2003) Complex of pregnancy-associated plasma protein-A and the proform of eosinophil major basic protein. Disulfide structure and carbohydrate attachment, J. Biol. Chem., 278, 2106-2117, https://doi.org/10.1074/jbc.M208777200.

    Article  CAS  PubMed  Google Scholar 

  7. Oxvig, C. (2015) The role of PAPP-A in the IGF system: location, location, location, J. Cell. Commun. Signal., 9, 177-187, https://doi.org/10.1007/s12079-015-0259-9.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Monget, P., Mazerbourg, S., Delpuech, T., Maurel, M. C., Manière, S., et al. (2003) Pregnancy-associated plasma protein-A is involved in insulin-like growth factor binding protein-2 (IGFBP-2) proteolytic degradation in bovine and porcine preovulatory follicles: identification of cleavage site and characterization of IGFBP-2 degradation, Biol. Reprod., 68, 77-86, https://doi.org/10.1095/biolreprod.102.007609.

    Article  CAS  PubMed  Google Scholar 

  9. Byun, D., Mohan, S., Yoo, M., Sexton, C., Baylink, D. J., and Qin, X. (2001) Pregnancy-associated plasma protein-A accounts for the insulin-like growth factor (IGF)-binding protein-4 (IGFBP-4) proteolytic activity in human pregnancy serum and enhances the mitogenic activity of IGF by degrading IGFBP-4 in vitro, J. Clin. Endocrinol. Metab., 86, 847-854, https://doi.org/10.1210/jcem.86.2.7223.

    Article  CAS  PubMed  Google Scholar 

  10. Gyrup, C., and Oxvig, C. (2007) Quantitative analysis of insulin-like growth factor-modulated proteolysis of insulin-like growth factor binding protein-4 and -5 by pregnancy-associated plasma protein-A, Biochemistry, 46, 1972-1980, https://doi.org/10.1021/bi062229i.

    Article  CAS  PubMed  Google Scholar 

  11. Lindsay, C. R., and Evans, T. J. (2008) The insulin-like growth factor system and its receptors: a potential novel anticancer target, Biologics, 2, 855-864, https://doi.org/10.2147/btt.s3841.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lawrence, J. B., Oxvig, C., Overgaard, M. T., Sottrup-Jensen, L., Gleich, G. J., et al. (1999) The insulin-like growth factor (IGF)-dependent IGF binding protein-4 protease secreted by human fibroblasts is pregnancy-associated plasma protein-A, Proc. Natl. Acad. Sci. USA, 96, 3149-3153, https://doi.org/10.1073/pnas.96.6.3149.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bayes-Genis, A., Conover, C. A., Overgaard, M. T., Bailey, K. R., Christiansen, M., et al. (2001) Pregnancy-associated plasma protein A as a marker of acute coronary syndromes, N. Engl. J. Med., 345, 1022-1029, https://doi.org/10.1056/NEJMoa003147.

    Article  CAS  PubMed  Google Scholar 

  14. Postnikov, A. B., Smolyanova, T. I., Kharitonov, A. V., Serebryanaya, D. V., Kozlovsky, S. V., et al. (2012) N-terminal and C-terminal fragments of IGFBP-4 as novel biomarkers for short-term risk assessment of major adverse cardiac events in patients presenting with ischemia, Clin. Biochem., 45, 519-524, https://doi.org/10.1016/j.clinbiochem.2011.12.030.

    Article  CAS  PubMed  Google Scholar 

  15. Hjortebjerg, R., Tarnow, L., Jorsal, A., Parving, H.-H., Rossing, P., Bjerre, M., and Frystyk, J (2015) IGFBP-4 fragments as markers of cardiovascular mortality in type 1 diabetes patients with and without nephropathy, J. Clin. Endocrin. Metab., 100, 3032-3040, https://doi.org/10.1210/jc.2015-2196.

    Article  CAS  Google Scholar 

  16. Konev, A. A., Kharitonov, A. V., Rozov, F. N., Altshuler, E. P., Serebryanaya, D. V., et al. (2020) CT-IGFBP-4 as a novel prognostic biomarker in acute heart failure, ESC Heart Fail., 7, 434-444, https://doi.org/10.1002/ehf2.12590.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Stepanova, O. V., Chadin, A. V., Kulikova, T. G., Masenko, V. P., and Tereschenko, S. N. (2012) The role of Rho-associated kinase in the formation of myofibrils and contractility of cardiomyocytes, Kardiol. Vestnik, 7, 10-14.

    Google Scholar 

  18. Laursen, L. S., Overgaard, M. T., Søe, R., Boldt, H. B., Sottrup-Jensen, L., et al. (2001) Pregnancy-associated plasma protein-A (PAPP-A) cleaves insulin-like growth factor binding protein (IGFBP)-5 independent of IGF: implications for the mechanism of IGFBP-4 proteolysis by PAPP-A, FEBS Lett., 504, 36-40, https://doi.org/10.1016/s0014-5793(01)02760-0.

    Article  CAS  PubMed  Google Scholar 

  19. Semenov, A. G., Tamm, N. N., Apple, F. S., Schulz, K. M., Love, S. A., et al. (2017) Searching for a BNP standard: glycosylated proBNP as a common calibrator enables improved comparability of commercial BNP immunoassays, Clin. Biochem., 50, 181-185, https://doi.org/10.1016/j.clinbiochem.2016.11.003.

    Article  CAS  PubMed  Google Scholar 

  20. Conover, C. A., Oxvig, C., Overgaard, M. T., Christiansen, M., and Giudice, L. C. (1999) Evidence that the insulin-like growth factor binding protein-4 protease in human ovarian follicular fluid is pregnancy associated plasma protein-A, J. Clin. Endocrinol. Metab., 84, 4742-4745, https://doi.org/10.1210/jcem.84.12.6342.

    Article  CAS  PubMed  Google Scholar 

  21. Mazerbourg, S., Overgaard, M. T., Oxvig, C., Christiansen, M., Conover, C. A., et al. (2001) Pregnancy-associated plasma protein-A (PAPP-A) in ovine, bovine, porcine, and equine ovarian follicles: involvement in IGF binding protein-4 proteolytic degradation and mRNA expression during follicular development, Endocrinology, 142, 5243-5253, https://doi.org/10.1210/endo.142.12.8517.

    Article  CAS  PubMed  Google Scholar 

  22. Conover, C. A., Faessen, G. F., Ilg, K. E., Chandrasekher, Y. A., Christiansen, M., et al. (2001) Pregnancy-associated plasma protein-A is the insulin-like growth factor binding protein-4 protease secreted by human ovarian granulosa cells and is a marker of dominant follicle selection and the corpus luteum, Endocrinology, 142, 2155, https://doi.org/10.1210/endo.142.5.8286.

    Article  CAS  PubMed  Google Scholar 

  23. Bayes-Genis, A., Schwartz, R. S., Lewis, D. A., Overgaard, M. T., Christiansen, M., et al. (2001) Insulin-like growth factor binding protein-4 protease produced by smooth muscle cells increases in the coronary artery after angioplasty, Arterioscler. Thromb. Vasc. Biol., 21, 335-341, https://doi.org/10.1161/01.atv.21.3.335.

    Article  CAS  PubMed  Google Scholar 

  24. Giudice, L. C., Conover, C. A., Bale, L., Faessen, G. H., Ilg, K., et al. (2002) Identification and regulation of the IGFBP-4 protease and its physiological inhibitor in human trophoblasts and endometrial stroma: evidence for paracrine regulation of IGF-II bioavailability in the placental bed during human implantation, J. Clin. Endocrinol. Metab., 87, 2359-2366, https://doi.org/10.1210/jcem.87.5.8448.

    Article  CAS  PubMed  Google Scholar 

  25. Conover, C. A., Bale, L. K., Frye, R. L., and Schaff, H. V. (2019) Cellular characterization of human epicardial adipose tissue: highly expressed PAPP-A regulates insulin-like growth factor I signaling in human cardiomyocytes, Physiol. Rep., 7, e14006, https://doi.org/10.14814/phy2.14006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Conover, C. A., Harrington, S. C., Bale, L. K. (2008) Differential regulation of pregnancy associated plasma protein-A in human coronary artery endothelial cells and smooth muscle cells, Growth Horm. IGF Res., 18, 213-20, https://doi.org/10.1016/j.ghir.2007.09.001.

    Article  CAS  PubMed  Google Scholar 

  27. D’Elia, P., Ionta, V., Chimenti, I., Angelini, F., Miraldi, F., et al. (2013) Analysis of pregnancy-associated plasma protein A production in human adult cardiac progenitor cells, BioMed Res. Int., 2013, 190178, https://doi.org/10.1155/2013/190178.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Banerjee, I., Fuseler, J. W., Price, R. L., Borg, T. K., and Baudino, T. A. (2007) Determination of cell types and numbers during cardiac development in the neonatal and adult rat and mouse, Am. J. Physiol. Heart Circ. Physiol., 293, H1883-H1891, https://doi.org/10.1152/ajpheart.00514.2007.

    Article  CAS  PubMed  Google Scholar 

  29. Laursen, L. S., Kjaer-Sorensen, K., Andersen, M. H., and Oxvig, C. (2007) Regulation of insulin-like growth factor (IGF) bioactivity by sequential proteolytic cleavage of IGF binding protein-4 and -5, Mol. Endocrinol., 21, 1246-1257, https://doi.org/10.1210/me.2006-0522.

    Article  CAS  PubMed  Google Scholar 

  30. Laursen, L. S., Overgaard, M. T., Nielsen, C. G., Boldt, H. B., Hopmann, K. H., et al. (2002) Substrate specificity of the metalloproteinase pregnancy-associated plasma protein-A (PAPP-A) assessed by mutagenesis and analysis of synthetic peptides: substrate residues distant from the scissile bond are critical for proteolysis, Biochem. J., 367, 31-40, https://doi.org/10.1042/BJ20020831.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ryall, K. A., Saucerman, J. J. (2012) Automated imaging reveals a concentration dependent delay in reversibility of cardiac myocyte hypertrophy, J. Mol. Cell. Cardiol., 53, 282-290, https://doi.org/10.1016/j.yjmcc.2012.04.016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Archer, C. R., Robinson, E. L., Drawnel, F. M., and Roderick, H. L. (2017) Endothelin-1 promotes hypertrophic remodelling of cardiac myocytes by activating sustained signalling and transcription downstream of endothelin type A receptors, Cell Signal., 36, 240-254, https://doi.org/10.1016/j.cellsig.2017.04.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Jen, H. L., Yin, W. H., Chen, J. W., and Lin, S. J. (2017) Endothelin-1-induced cell hypertrophy in cardiomyocytes is improved by fenofibrate: possible roles of adiponectin, J. Atheroscler. Thromb., 24, 508-517, https://doi.org/10.5551/jat.36368.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Higazi, D. R., Fearnley, C. J., Drawnel, F. M., Talasila, A., Corps, E. M., et al. (2009) Ca2+ release is a nexus for hypertrophic signaling in cardiac myocytes, Mol. Cell, 33, 472-482, https://doi.org/10.1016/j.molcel.2009.02.005.

    Article  CAS  PubMed  Google Scholar 

  35. Yue, T. L., Gu, J. L., Wang, C., Reith, A. D., Lee, J. C., et al. (2000) Extracellular signal-regulated kinase plays an essential role in hypertrophic agonists, endothelin-1 and phenylephrine-induced cardiomyocyte hypertrophy, J. Biol. Chem., 275, 37895-37901, https://doi.org/10.1074/jbc.M007037200.

    Article  CAS  PubMed  Google Scholar 

  36. Yamazaki, T., Komuro, I., Kudoh, S., Zou, Y., Shiojima, I., et al. (1996) Endothelin-1 is involved in mechanical stress-induced cardiomyocyte hypertrophy, J. Biol. Chem., 271, 3221-3228, https://doi.org/10.1074/jbc.271.6.3221.

    Article  CAS  PubMed  Google Scholar 

  37. Nakahashi, T., Fukuo, K., Inoue, T., Morimoto, S., Hata, S., et al. (1995) Endothelin-1 enhances nitric oxide-induced cytotoxicity in vascular smooth muscle, Hypertension, 25, 744-747, https://doi.org/10.1161/01.hyp.25.4.744.

    Article  CAS  PubMed  Google Scholar 

  38. Piacentini, L., Gray, M., Honbo, N. Y., Chentoufi, J., Bergman, M., Karliner, J. S. (2000) Endothelin-1 stimulates cardiac fibroblast proliferation through activation of protein kinase C, J. Mol. Cell Cardiol., 32, 565-576, https://doi.org/10.1006/jmcc.2000.1109.

    Article  CAS  PubMed  Google Scholar 

  39. Hjortebjerg, R., Lindberg, S., Pedersen, S., Mogelvang, R., Jensen, J. S., et al. (2017) Insulin‐like growth factor binding protein 4 fragments provide incremental prognostic Information on cardiovascular events in patients with ST‐segment elevation myocardial infarction, J. Am. Heart Assoc., 6, e005358, https://doi.org/10.1161/JAHA.116.005358.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Makkos, A., Szántai, Á., Pálóczi, J., Pipis, J., Kiss, B., et al. (2020) A Comorbidity model of myocardial ischemia/reperfusion injury and hypercholesterolemia in rat cardiac myocyte cultures, Front. Physiol., 10, 1564, https://doi.org/10.3389/fphys.2019.01564.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Ariyasinghe, N. R., Lyra-Leite, D. M., and McCain, M. L. (2018) Engineering cardiac microphysiological systems to model pathological extracellular matrix remodeling, Am. J. Physiol. Heart Circ. Physiol., 315, H771-H789, https://doi.org/10.1152/ajpheart.00110.2018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Belostotskaya, G. B., and Golovanova, T. A. (2014) Characterization of contracting cardiomyocyte colonies in the primary culture of neonatal rat myocardial cells: a model of in vitro cardiomyogenesis, Cell Cycle, 13, 910-918, https://doi.org/10.4161/cc.27768.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Higashi, Y., Gautam, S., Delafontaine, P., and Sukhanov, S. (2019) IGF-1 and cardiovascular disease, Growth Horm. IGF Res., 45, 6-16, https://doi.org/10.1016/j.ghir.2019.01.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Mohamed-Ali, V., and Pinkney, J. (2002) Therapeutic potential of insulin-like growth factor-1 in patients with diabetes mellitus, Treat. Endocrinol., 1, 399-410, https://doi.org/10.2165/00024677-200201060-00005.

    Article  CAS  PubMed  Google Scholar 

  45. Sádaba, M. C., Martín-Estal, I., Puche, J. E., and Castilla-Cortázar, I. (2016) Insulin-like growth factor 1 (IGF-1) therapy: mitochondrial dysfunction and diseases, Biochim. Biophys. Acta, 1862, 1267-1278, https://doi.org/10.1016/j.bbadis.2016.03.010.

    Article  CAS  PubMed  Google Scholar 

  46. Vinciguerra, M., Santini, M. P., Claycomb, W. C., Ladurner, A. G., and Rosenthal, N. (2009) Local IGF-1 isoform protects cardiomyocytes from hypertrophic and oxidative stresses via SirT1 activity, Aging (Albany NY), 2, 43-62, https://doi.org/10.18632/aging.100107.

    Article  Google Scholar 

  47. Yeves, A. M., Burgos, J. I., Medina, A. J., Villa-Abrille, M. C., and Ennis, I. L. (2018) Cardioprotective role of IGF-1 in the hypertrophied myocardium of the spontaneously hypertensive rats: a key effect on NHE-1 activity, Acta Physiol. (Oxf), 224, e13164, https://doi.org/10.1111/apha.13092.

    Article  CAS  Google Scholar 

  48. Sui, Y., Zhang, W., Tang, T., Gao, L., Cao, T., et al. (2020) Insulin-like growth factor-II overexpression accelerates parthenogenetic stem cell differentiation into cardiomyocytes and improves cardiac function after acute myocardial infarction in mice, Stem Cell Res. Ther., 11, 86, https://doi.org/10.1186/s13287-020-1575-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Lin, M., Liu, X., Zheng, H., Huang, X., Wu, Y., et al. (2020) IGF-1 enhances BMSC viability, migration, and anti-apoptosis in myocardial infarction via secreted frizzled-related protein 2 pathway, Stem Cell Res. Ther., 11, 22, https://doi.org/10.1186/s13287-019-1544-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Adachi, S., Ito, H., Akimoto, H., Tanaka, M., Fujisaki, H., et al. (1994) Insulin-like growth factor-II induces hypertrophy with increased expression of muscle specific genes in cultured rat cardiomyocytes, J. Mol. Cell. Cardiol., 26, 789-795, https://doi.org/10.1006/jmcc.1994.1096.

    Article  CAS  PubMed  Google Scholar 

  51. Carrasco, L., Cea, P., Rocco, P., Peña-Oyarzún, D., Rivera-Mejias, P., et al. (2014) Role of heterotrimeric G protein and calcium in cardiomyocyte hypertrophy induced by IGF-1, J. Cell Biochem., 115, 712-720, https://doi.org/10.1002/jcb.24712.

    Article  CAS  PubMed  Google Scholar 

  52. Ito, H., Hiroe, M., Hirata, Y., Tsujino, M., Adachi, S., et al. (1993) Insulin-like growth factor-I induces hypertrophy with enhanced expression of muscle specific genes in cultured rat cardiomyocytes, Circulation, 87, 1715-1721, https://doi.org/10.1161/01.cir.87.5.1715.

    Article  CAS  PubMed  Google Scholar 

  53. Huang, C. Y., Hao, L. Y., and Buetow, D. E. (2002) Insulin-like growth factor-II induces hypertrophy of adult cardiomyocytes via two alternative pathways, Cell. Biol. Int., 26, 737-739, https://doi.org/10.1006/cbir.2002.0919.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors express their sincere gratitude to Doctor of Biological Sciences, Professor N. B. Gusev and V. E. Adashev for valuable remarks and comments that significantly improved the manuscript.

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Authors and Affiliations

  1. Department of Biochemistry, Faculty of Biology, Lomonosov Moscow State University, 119234, Moscow, Russia

    Daria V. Serebryanaya, Daria A. Adasheva, Ivan A. Katrukha, Alexander B. Postnikov & Alexey G. Katrukha

  2. HyTest Ltd., 20520, Turku, Finland

    Alexey A. Konev, Ivan A. Katrukha, Alexander B. Postnikov & Alexey G. Katrukha

  3. Department of Human and Animal Physiology, Faculty of Biology, Lomonosov Moscow State University, 119234, Moscow, Russia

    Marina M. Artemieva & Natalia A. Medvedeva

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  1. Daria V. Serebryanaya
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Correspondence to Daria V. Serebryanaya.

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Serebryanaya, D.V., Adasheva, D.A., Konev, A.A. et al. IGFBP-4 Proteolysis by PAPP-A in a Primary Culture of Rat Neonatal Cardiomyocytes under Normal and Hypertrophic Conditions. Biochemistry Moscow 86, 1395–1406 (2021). https://doi.org/10.1134/S0006297921110043

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