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Protein Aggregation and Cataract: Role of Age-Related Modifications and Mutations in α-Crystallins

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Abstract

Cataract is a major cause of blindness. Due to the lack of protein turnover, lens proteins accumulate age-related and environmental modifications that alter their native conformation, leading to the formation of aggregation-prone intermediates, as well as insoluble and light-scattering aggregates, thus compromising lens transparency. The lens protein, α-crystallin, is a molecular chaperone that prevents protein aggregation, thereby maintaining lens transparency. However, mutations or post-translational modifications, such as oxidation, deamidation, truncation and crosslinking, can render α-crystallins ineffective and lead to the disease exacerbation. Here, we describe such mutations and alterations, as well as their consequences. Age-related modifications in α-crystallins affect their structure, oligomerization, and chaperone function. Mutations in α-crystallins can lead to the aggregation/intracellular inclusions attributable to the perturbation of structure and oligomeric assembly and resulting in the rearrangement of aggregation-prone regions. Such rearrangements can lead to the exposure of hitherto buried aggregation-prone regions, thereby populating aggregation-prone state(s) and facilitating amorphous/amyloid aggregation and/or inappropriate interactions with cellular components. Investigations of the mutation-induced changes in the structure, oligomer assembly, aggregation mechanisms, and interactomes of α-crystallins will be useful in fighting protein aggregation-related diseases.

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Abbreviations

ACD:

alpha crystallin domain

CTE:

C-terminal extension

NTD:

N-terminal domain

sHsp:

small heat shock protein

References

  1. Chou, C. F., Cotch, M. F., Vitale, S., Zhang, X., Klein, R., et al. (2013) Age-related eye diseases and visual impairment among U.S. adults, Am. J. Prev. Med., 45, 29-35, https://doi.org/10.1016/j.amepre.2013.02.018.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Bloemendal, H., de Jong, W., Jaenicke, R., Lubsen, N. H., Slingsby, C., et al. (2004) Ageing and vision: structure, stability and function of lens crystallins, Prog. Biophys. Mol. Biol., 86, 407-485, https://doi.org/10.1016/j.pbiomolbio.2003.11.012.

    Article  CAS  PubMed  Google Scholar 

  3. Delaye, M., and Tardieu, A. (1983) Short-range order of crystallin proteins accounts for eye lens transparency, Nature, 302, 415-417, https://doi.org/10.1038/302415a0.

    Article  CAS  PubMed  Google Scholar 

  4. Benedek, G. B. (1971) Theory of transparency of the eye, Appl. Opt., 10, 459-473, https://doi.org/10.1364/AO.10.000459.

    Article  CAS  PubMed  Google Scholar 

  5. Hanson, S. R., Hasan, A., Smith, D. L., and Smith, J. B. (2000) The major in vivo modifications of the human water-insoluble lens crystallins are disulfide bonds, deamidation, methionine oxidation and backbone cleavage, Exp. Eye Res., 71, 195-207, https://doi.org/10.1006/exer.2000.0868.

    Article  CAS  PubMed  Google Scholar 

  6. Harding, J. J. (2002) Viewing molecular mechanisms of ageing through a lens, Ageing Res. Rev., 1, 465-479, https://doi.org/10.1016/s1568-1637(02)00012-0.

    Article  CAS  PubMed  Google Scholar 

  7. Zhang, T. O., Alperstein, A. M., and Zanni, M. T. (2017) Amyloid beta-sheet secondary structure identified in UV-induced cataracts of porcine lenses using 2D IR spectroscopy, J. Mol. Biol., 429, 1705-1721, https://doi.org/10.1016/j.jmb.2017.04.014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Alperstein, A. M., Ostrander, J. S., Zhang, T. O., and Zanni, M. T. (2019) Amyloid found in human cataracts with two-dimensional infrared spectroscopy, Proc. Natl. Acad. Sci. USA, 116, 6602-6607, https://doi.org/10.1073/pnas.1821534116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Alperstein, A. M., Molnar, K. S., Dicke, S. S., Farrell, K. M., Makley, L. N., et al. (2021) Analysis of amyloid-like secondary structure in the Cryab-R120G knock-in mouse model of hereditary cataracts by two-dimensional infrared spectroscopy, PLoS One, 16, e0257098, https://doi.org/10.1371/journal.pone.0257098.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Mörner, C. T. (1894) Untersuchung der Proteїnsubstanzen in den leichtbrechenden Medien des Auges I [in German], bchm, 18, 61-106, https://doi.org/10.1515/bchm1.1894.18.1.61.

    Article  Google Scholar 

  11. Roy, D., and Spector, A. (1976) Absence of low-molecular-weight alpha crystallin in nuclear region of old human lenses, Proc. Natl. Acad. Sci. USA, 73, 3484-3487, https://doi.org/10.1073/pnas.73.10.3484.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Horwitz, J., Bova, M. P., Ding, L. L., Haley, D. A., and Stewart, P. L. (1999) Lens alpha-crystallin: Function and structure, Eye (Lond), 13 (Pt. 3b), 403-408, https://doi.org/10.1038/eye.1999.114.

    Article  Google Scholar 

  13. Bakthisaran, R., Tangirala, R., and Rao, Ch. M. (2015) Small heat shock proteins: Role in cellular functions and pathology, Biochim. Biophys. Acta, 1854, 291-319, https://doi.org/10.1016/j.bbapap.2014.12.019.

    Article  CAS  PubMed  Google Scholar 

  14. Kappe, G., Franck, E., Verschuure, P., Boelens, W. C., Leunissen, J. A., et al. (2003) The human genome encodes 10 alpha-crystallin-related small heat shock proteins: HspB1-10, Cell Stress Chaperones, 8, 53-61, https://doi.org/10.1379/1466-1268(2003)8<53:thgecs>2.0.co;2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ingolia, T. D., and Craig, E. A. (1982) Four small Drosophila heat shock proteins are related to each other and to mammalian alpha-crystallin, Proc. Natl. Acad. Sci. USA, 79, 2360-2364, https://doi.org/10.1073/pnas.79.7.2360.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Horwitz, J. (1992) Alpha-crystallin can function as a molecular chaperone, Proc. Natl. Acad. Sci. USA, 89, 10449-10453, https://doi.org/10.1073/pnas.89.21.10449.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Raman, B., and Rao, C. M. (1994) Chaperone-like activity and quaternary structure of alpha-crystallin, J. Biol. Chem., 269, 27264-27268.

    Article  CAS  Google Scholar 

  18. Raman, B., Ramakrishna, T., and Rao, C. M. (1995) Temperature dependent chaperone-like activity of alpha-crystallin, FEBS Lett., 365, 133-136, https://doi.org/10.1016/0014-5793(95)00440-k.

    Article  CAS  PubMed  Google Scholar 

  19. Rajaraman, K., Raman, B., Ramakrishna, T., and Rao, C. M. (1998) The chaperone-like alpha-crystallin forms a complex only with the aggregation-prone molten globule state of alpha-lactalbumin, Biochem. Biophys. Res. Commun., 249, 917-921, https://doi.org/10.1006/bbrc.1998.9242.

    Article  CAS  PubMed  Google Scholar 

  20. Raman, B., and Rao, C. M. (1997) Chaperone-like activity and temperature-induced structural changes of alpha-crystallin, J. Biol. Chem., 272, 23559-23564, https://doi.org/10.1074/jbc.272.38.23559.

    Article  CAS  PubMed  Google Scholar 

  21. Datta, S. A., and Rao, C. M. (1999) Differential temperature-dependent chaperone-like activity of alphaA- and alphaB-crystallin homoaggregates, J. Biol. Chem., 274, 34773-34778, https://doi.org/10.1074/jbc.274.49.34773.

    Article  CAS  PubMed  Google Scholar 

  22. Rajaraman, K., Raman, B., Ramakrishna, T., and Rao, C. M. (2001) Interaction of human recombinant alphaA- and alphaB-crystallins with early and late unfolding intermediates of citrate synthase on its thermal denaturation, FEBS Lett., 497, 118-123, https://doi.org/10.1016/s0014-5793(01)02451-6.

    Article  CAS  PubMed  Google Scholar 

  23. Goenka, S., Raman, B., Ramakrishna, T., and Rao, C. M. (2001) Unfolding and refolding of a quinone oxidoreductase: alpha-crystallin, a molecular chaperone, assists its reactivation, Biochem. J., 359, 547-556, https://doi.org/10.1042/0264-6021:3590547.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sathish, H. A., Koteiche, H. A., and McHaourab, H. S. (2004) Binding of destabilized betaB2-crystallin mutants to alpha-crystallin: The role of a folding intermediate, J. Biol. Chem., 279, 16425-16432, https://doi.org/10.1074/jbc.M313402200.

    Article  CAS  PubMed  Google Scholar 

  25. McHaourab, H. S., Dodson, E. K., and Koteiche, H. A. (2002) Mechanism of chaperone function in small heat shock proteins. Two-mode binding of the excited states of T4 lysozyme mutants by alphaA-crystallin, J. Biol. Chem., 277, 40557-40566, https://doi.org/10.1074/jbc.M206250200.

    Article  CAS  PubMed  Google Scholar 

  26. Koteiche, H. A., and McHaourab, H. S. (2003) Mechanism of chaperone function in small heat-shock proteins. Phosphorylation-induced activation of two-mode binding in alphaB-crystallin, J. Biol. Chem., 278, 10361-10367, https://doi.org/10.1074/jbc.M211851200.

    Article  CAS  PubMed  Google Scholar 

  27. Hatters, D. M., Lindner, R. A., Carver, J. A., and Howlett, G. J. (2001) The molecular chaperone, alpha-crystallin, inhibits amyloid formation by apolipoprotein C-II, J. Biol. Chem., 276, 33755-33761, https://doi.org/10.1074/jbc.M105285200.

    Article  CAS  PubMed  Google Scholar 

  28. Devlin, G. L., Carver, J. A., and Bottomley, S. P. (2003) The selective inhibition of serpin aggregation by the molecular chaperone, alpha-crystallin, indicates a nucleation-dependent specificity, J. Biol. Chem., 278, 48644-48650, https://doi.org/10.1074/jbc.M308376200.

    Article  CAS  PubMed  Google Scholar 

  29. Raman, B., Ban, T., Sakai, M., Pasta, S. Y., Ramakrishna, T., et al. (2005) AlphaB-crystallin, a small heat-shock protein, prevents the amyloid fibril growth of an amyloid beta-peptide and beta2-microglobulin, Biochem. J., 392, 573-581, https://doi.org/10.1042/BJ20050339.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Shammas, S. L., Waudby, C. A., Wang, S., Buell, A. K., Knowles, T. P., et al. (2011) Binding of the molecular chaperone alphaB-crystallin to Abeta amyloid fibrils inhibits fibril elongation, Biophys. J., 101, 1681-1689, https://doi.org/10.1016/j.bpj.2011.07.056.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Narayan, P., Meehan, S., Carver, J. A., Wilson, M. R., Dobson, C. M., et al. (2012) Amyloid-beta oligomers are sequestered by both intracellular and extracellular chaperones, Biochemistry, 51, 9270-9276, https://doi.org/10.1021/bi301277k.

    Article  CAS  PubMed  Google Scholar 

  32. Haslbeck, M., Peschek, J., Buchner, J., and Weinkauf, S. (2016) Structure and function of alpha-crystallins: Traversing from in vitro to in vivo, Biochim. Biophys. Acta, 1860, 149-166, https://doi.org/10.1016/j.bbagen.2015.06.008.

    Article  CAS  PubMed  Google Scholar 

  33. Santhoshkumar, P., Murugesan, R., and Sharma, K. K. (2009) Deletion of (54)FLRAPSWF(61) residues decreases the oligomeric size and enhances the chaperone function of alphaB-crystallin, Biochemistry, 48, 5066-5073, https://doi.org/10.1021/bi900085v.

    Article  CAS  PubMed  Google Scholar 

  34. Pasta, S. Y., Raman, B., Ramakrishna, T., and Rao, Ch. M. (2003) Role of the conserved SRLFDQFFG region of alpha-crystallin, a small heat shock protein. Effect on oligomeric size, subunit exchange, and chaperone-like activity, J. Biol. Chem., 278, 51159-51166, https://doi.org/10.1074/jbc.M307523200.

    Article  CAS  PubMed  Google Scholar 

  35. Jehle, S., Vollmar, B. S., Bardiaux, B., Dove, K. K., Rajagopal, P., et al. (2011) N-terminal domain of alphaB-crystallin provides a conformational switch for multimerization and structural heterogeneity, Proc. Natl. Acad. Sci. USA, 108, 6409-6414, https://doi.org/10.1073/pnas.1014656108.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Pasta, S. Y., Raman, B., Ramakrishna, T., and Rao, Ch., M. (2002) Role of the C-terminal extensions of alpha-crystallins. Swapping the C-terminal extension of alpha-crystallin to alphaB-crystallin results in enhanced chaperone activity, J. Biol. Chem., 277, 45821-45828, https://doi.org/10.1074/jbc.M206499200.

    Article  CAS  PubMed  Google Scholar 

  37. Treweek, T. M., Ecroyd, H., Williams, D. M., Meehan, S., Carver, J. A., and Walker, M. J. (2007) Site-directed mutations in the C-terminal extension of human alphaB-crystallin affect chaperone function and block amyloid fibril formation, PLoS One, 2, e1046, https://doi.org/10.1371/journal.pone.0001046.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kumar, L. V., and Rao, C. M. (2000) Domain swapping in human alpha A and alpha B crystallins affects oligomerization and enhances chaperone-like activity, J. Biol. Chem., 275, 22009-22013, https://doi.org/10.1074/jbc.M003307200.

    Article  CAS  PubMed  Google Scholar 

  39. Peschek, J., Braun, N., Franzmann, T. M., Georgalis, Y., Haslbeck, M., et al. (2009) The eye lens chaperone alpha-crystallin forms defined globular assemblies, Proc. Natl. Acad. Sci. USA, 106, 13272-13277, https://doi.org/10.1073/pnas.0902651106.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Kaiser, C. J. O., Peters, C., Schmid, P. W. N., Stavropoulou, M., Zou, J., et al. (2019) The structure and oxidation of the eye lens chaperone alphaA-crystallin, Nat. Struct. Mol. Biol., 26, 1141-1150, https://doi.org/10.1038/s41594-019-0332-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. McCarty, C. A., and Taylor, H. R. (2002) A review of the epidemiologic evidence linking ultraviolet radiation and cataracts, Dev. Ophthalmol., 35, 21-31, https://doi.org/10.1159/000060807.

    Article  PubMed  Google Scholar 

  42. Kamei, A. (1990) Characterization of water-insoluble proteins in normal and cataractous human lens, Jpn. J. Ophthalmol., 34, 216-224.

    CAS  PubMed  Google Scholar 

  43. Harrington, V., McCall, S., Huynh, S., Srivastava, K., and Srivastava, O. P. (2004) Crystallins in water soluble-high molecular weight protein fractions and water insoluble protein fractions in aging and cataractous human lenses, Mol. Vis., 10, 476-489.

    CAS  PubMed  Google Scholar 

  44. Sharma, K. K., and Santhoshkumar, P. (2009) Lens aging: Effects of crystallins, Biochim. Biophys. Acta, 1790, 1095-1108, https://doi.org/10.1016/j.bbagen.2009.05.008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wilmarth, P. A., Tanner, S., Dasari, S., Nagalla, S. R., Riviere, M. A., et al. (2006) Age-related changes in human crystallins determined from comparative analysis of post-translational modifications in young and aged lens: Does deamidation contribute to crystallin insolubility? J. Proteome Res., 5, 2554-2566, https://doi.org/10.1021/pr050473a.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Lapko, V. N., Smith, D. L., and Smith, J. B. (2001) In vivo carbamylation and acetylation of water-soluble human lens alphaB-crystallin lysine 92, Protein Sci., 10, 1130-1136, https://doi.org/10.1110/ps.40901.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Taylor, H. R., West, S. K., Rosenthal, F. S., Munoz, B., Newland, H. S., et al. (1988) Effect of ultraviolet radiation on cataract formation, N. Engl. J. Med., 319, 1429-1433, https://doi.org/10.1056/NEJM198812013192201.

    Article  CAS  PubMed  Google Scholar 

  48. Korlimbinis, A., Hains, P. G., Truscott, R. J., and Aquilina, J. A. (2006) 3-Hydroxykynurenine oxidizes alpha-crystallin: Potential role in cataractogenesis, Biochemistry, 45, 1852-1860, https://doi.org/10.1021/bi051737+.

    Article  CAS  PubMed  Google Scholar 

  49. Anbaraki, A., Ghahramani, M., Muranov, K. O., Kurganov, B. I., and Yousefi, R. (2018) Structural and functional alteration of human alphaA-crystallin after exposure to full spectrum solar radiation and preventive role of lens antioxidants, Int. J. Biol. Macromol., 118, 1120-1130, https://doi.org/10.1016/j.ijbiomac.2018.06.136.

    Article  CAS  PubMed  Google Scholar 

  50. Lin, S. Y., Ho, C. J., and Li, M. J. (1999) UV-B-induced secondary conformational changes in lens alpha-crystallin, J. Photochem. Photobiol. B, 49, 29-34, https://doi.org/10.1016/S1011-1344(99)00010-X.

    Article  CAS  PubMed  Google Scholar 

  51. Rajan, S., Horn, C., and Abraham, E. C. (2006) Effect of oxidation of alphaA- and alphaB-crystallins on their structure, oligomerization and chaperone function, Mol. Cell. Biochem., 288, 125-134, https://doi.org/10.1007/s11010-006-9128-4.

    Article  CAS  PubMed  Google Scholar 

  52. Chaves, J. M., Srivastava, K., Gupta, R., and Srivastava, O. P. (2008) Structural and functional roles of deamidation and/or truncation of N- or C-termini in human alpha A-crystallin, Biochemistry, 47, 10069-10083, https://doi.org/10.1021/bi8001902.

    Article  CAS  PubMed  Google Scholar 

  53. Gupta, R., and Srivastava, O. P. (2004) Deamidation affects structural and functional properties of human alphaA-crystallin and its oligomerization with alphaB-crystallin, J. Biol. Chem., 279, 44258-44269, https://doi.org/10.1074/jbc.M405648200.

    Article  CAS  PubMed  Google Scholar 

  54. Gupta, R., and Srivastava, O. P. (2004) Effect of deamidation of asparagine 146 on functional and structural properties of human lens alphaB-crystallin, Invest. Ophthalmol. Vis. Sci., 45, 206-214, https://doi.org/10.1167/iovs.03-0720.

    Article  PubMed  Google Scholar 

  55. Grey, A. C., and Schey, K. L. (2009) Age-related changes in the spatial distribution of human lens alpha-crystallin products by MALDI imaging mass spectrometry, Invest. Ophthalmol. Vis. Sci., 50, 4319-4329, https://doi.org/10.1167/iovs.09-3522.

    Article  PubMed  Google Scholar 

  56. MacCoss, M. J., McDonald, W. H., Saraf, A., Sadygov, R., Clark, J. M., et al. (2002) Shotgun identification of protein modifications from protein complexes and lens tissue, Proc. Natl. Acad. Sci. USA, 99, 7900-7905, https://doi.org/10.1073/pnas.122231399.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Huang, C. H., Wang, Y. T., Tsai, C. F., Chen, Y. J., Lee, J. S., et al. (2011) Phosphoproteomics characterization of novel phosphorylated sites of lens proteins from normal and cataractous human eye lenses, Mol. Vis., 17, 186-198.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Bakthisaran, R., Akula, K. K., Tangirala, R., and Rao, Ch., M. (2016) Phosphorylation of alphaB-crystallin: Role in stress, aging and patho-physiological conditions, Biochim. Biophys. Acta, 1860, 167-182, https://doi.org/10.1016/j.bbagen.2015.09.017.

    Article  CAS  PubMed  Google Scholar 

  59. Muranova, L. K., Sudnitsyna, M. V., and Gusev, N. B. (2018) alphaB-crystallin phosphorylation: advances and problems, Biochemistry (Moscow), 83, 1196-1206, https://doi.org/10.1134/S000629791810005X.

    Article  CAS  Google Scholar 

  60. Carver, J. A., Nicholls, K. A., Aquilina, J. A., and Truscott, R. J. (1996) Age-related changes in bovine alpha-crystallin and high-molecular-weight protein, Exp. Eye Res., 63, 639-647, https://doi.org/10.1006/exer.1996.0158.

    Article  CAS  PubMed  Google Scholar 

  61. Den Engelsman, J., Gerrits, D., de Jong, W. W., Robbins, J., Kato, K., et al. (2005) Nuclear import of {alpha}B-crystallin is phosphorylation-dependent and hampered by hyperphosphorylation of the myopathy-related mutant R120G, J. Biol. Chem., 280, 37139-37148, https://doi.org/10.1074/jbc.M504106200.

    Article  CAS  PubMed  Google Scholar 

  62. Simon, S., Fontaine, J. M., Martin, J. L., Sun, X., Hoppe, A. D., et al. (2007) Myopathy-associated alphaB-crystallin mutants: Abnormal phosphorylation, intracellular location, and interactions with other small heat shock proteins, J. Biol. Chem., 282, 34276-34287, https://doi.org/10.1074/jbc.M703267200.

    Article  CAS  PubMed  Google Scholar 

  63. Lyon, Y. A., Sabbah, G. M., and Julian, R. R. (2018) Differences in alpha-Crystallin isomerization reveal the activity of protein isoaspartyl methyltransferase (PIMT) in the nucleus and cortex of human lenses, Exp. Eye Res., 171, 131-141, https://doi.org/10.1016/j.exer.2018.03.018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Takata, T., and Fujii, N. (2016) Isomerization of Asp residues plays an important role in alphaA-crystallin dissociation, FEBS J., 283, 850-859, https://doi.org/10.1111/febs.13635.

    Article  CAS  PubMed  Google Scholar 

  65. Hooi, M. Y., Raftery, M. J., and Truscott, R. J. (2013) Age-dependent racemization of serine residues in a human chaperone protein, Protein Sci., 22, 93-100, https://doi.org/10.1002/pro.2191.

    Article  CAS  PubMed  Google Scholar 

  66. Lyon, Y. A., Collier, M. P., Riggs, D. L., Degiacomi, M. T., Benesch, J. L. P., et al. (2019) Structural and functional consequences of age-related isomerization in alpha-crystallins, J. Biol. Chem., 294, 7546-7555, https://doi.org/10.1074/jbc.RA118.007052.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Lyons, T. J., Silvestri, G., Dunn, J. A., Dyer, D. G., and Baynes, J. W. (1991) Role of glycation in modification of lens crystallins in diabetic and nondiabetic senile cataracts, Diabetes, 40, 1010-1015, https://doi.org/10.2337/diab.40.8.1010.

    Article  CAS  PubMed  Google Scholar 

  68. Thorpe, S. R., and Baynes, J. W. (1996) Role of the Maillard reaction in diabetes mellitus and diseases of aging, Drugs Aging, 9, 69-77, https://doi.org/10.2165/00002512-199609020-00001.

    Article  CAS  PubMed  Google Scholar 

  69. Stevens, V. J., Rouzer, C. A., Monnier, V. M., and Cerami, A. (1978) Diabetic cataract formation: Potential role of glycosylation of lens crystallins, Proc. Natl. Acad. Sci. USA, 75, 2918-2922, https://doi.org/10.1073/pnas.75.6.2918.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Kumar, P. A., Kumar, M. S., and Reddy, G. B. (2007) Effect of glycation on alpha-crystallin structure and chaperone-like function, Biochem. J., 408, 251-258, https://doi.org/10.1042/BJ20070989.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Schey, K. L., Wang, Z., Friedrich, M. G., Garland, D. L., and Truscott, R. J. W. (2020) Spatiotemporal changes in the human lens proteome: Critical insights into long-lived proteins, Prog. Retin. Eye Res., 76, 100802, https://doi.org/10.1016/j.preteyeres.2019.100802.

    Article  CAS  PubMed  Google Scholar 

  72. Kamei, A., Iwase, H., and Masuda, K. (1997) Cleavage of amino acid residue(s) from the N-terminal region of alpha A- and alpha B-crystallins in human crystalline lens during aging, Biochem. Biophys. Res. Commun., 231, 373-378, https://doi.org/10.1006/bbrc.1997.6105.

    Article  CAS  PubMed  Google Scholar 

  73. Jimenez-Asensio, J., Colvis, C. M., Kowalak, J. A., Duglas-Tabor, Y., Datiles, M. B., et al. (1999) An atypical form of alphaB-crystallin is present in high concentration in some human cataractous lenses. Identification and characterization of aberrant N- and C-terminal processing, J. Biol. Chem., 274, 32287-32294, https://doi.org/10.1074/jbc.274.45.32287.

    Article  CAS  PubMed  Google Scholar 

  74. Takemoto, L., Emmons, T., and Horwitz, J. (1993) The C-terminal region of alpha-crystallin: involvement in protection against heat-induced denaturation, Biochem. J., 294 (Pt. 2), 435-438, https://doi.org/10.1042/bj2940435.

    Article  Google Scholar 

  75. Santhoshkumar, P., Udupa, P., Murugesan, R., and Sharma, K. K. (2008) Significance of interactions of low molecular weight crystallin fragments in lens aging and cataract formation, J. Biol. Chem., 283, 8477-8485, https://doi.org/10.1074/jbc.M705876200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Su, S. P., McArthur, J. D., and Andrew Aquilina, J. (2010) Localization of low molecular weight crystallin peptides in the aging human lens using a MALDI mass spectrometry imaging approach, Exp. Eye Res., 91, 97-103, https://doi.org/10.1016/j.exer.2010.04.010.

    Article  CAS  PubMed  Google Scholar 

  77. Kannan, R., Santhoshkumar, P., Mooney, B. P., and Sharma, K. K. (2013) The alphaA66-80 peptide interacts with soluble alpha-crystallin and induces its aggregation and precipitation: A contribution to age-related cataract formation, Biochemistry, 52, 3638-3650, https://doi.org/10.1021/bi301662w.

    Article  CAS  PubMed  Google Scholar 

  78. Raju, M., Santhoshkumar, P., and Sharma, K. K. (2017) Lens endogenous peptide alphaA66-80 generates hydrogen peroxide and induces cell apoptosis, Aging Dis., 8, 57-70, https://doi.org/10.14336/AD.2016.0805.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Nagaraj, R. H., Nahomi, R. B., Shanthakumar, S., Linetsky, M., Padmanabha, S., et al. (2012) Acetylation of alphaA-crystallin in the human lens: effects on structure and chaperone function, Biochim. Biophys. Acta, 1822, 120-129, https://doi.org/10.1016/j.bbadis.2011.11.011.

    Article  CAS  PubMed  Google Scholar 

  80. Wang, Z., Friedrich, M. G., Truscott, R. J. W., and Schey, K. L. (2019) Cleavage C-terminal to Asp leads to covalent crosslinking of long-lived human proteins, Biochim. Biophys. Acta Proteins Proteom., 1867, 831-839, https://doi.org/10.1016/j.bbapap.2019.06.009.

    Article  CAS  PubMed  Google Scholar 

  81. Litt, M., Kramer, P., LaMorticella, D. M., Murphey, W., Lovrien, E. W., et al. (1998) Autosomal dominant congenital cataract associated with a missense mutation in the human alpha crystallin gene CRYAA, Hum. Mol. Genet., 7, 471-474, https://doi.org/10.1093/hmg/7.3.471.

    Article  CAS  PubMed  Google Scholar 

  82. Pras, E., Frydman, M., Levy-Nissenbaum, E., Bakhan, T., Raz, J., et al. (2000) A nonsense mutation (W9X) in CRYAA causes autosomal recessive cataract in an inbred Jewish Persian family, Invest. Ophthalmol. Vis. Sci., 41, 3511-3515.

    CAS  PubMed  Google Scholar 

  83. Hansen, L., Yao, W., Eiberg, H., Kjaer, K. W., Baggesen, K., et al. (2007) Genetic heterogeneity in microcornea-cataract: Five novel mutations in CRYAA, CRYGD, and GJA8, Invest. Ophthalmol. Vis. Sci., 48, 3937-3944, https://doi.org/10.1167/iovs.07-0013.

    Article  PubMed  Google Scholar 

  84. Devi, R. R., Yao, W., Vijayalakshmi, P., Sergeev, Y. V., Sundaresan, P., et al. (2008) Crystallin gene mutations in Indian families with inherited pediatric cataract, Mol. Vis., 14, 1157-1170.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Song, Z., Si, N., and Xiao, W. (2018) A novel mutation in the CRYAA gene associated with congenital cataract and microphthalmia in a Chinese family, BMC Med. Genet., 19, 190, https://doi.org/10.1186/s12881-018-0695-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Graw, J., Klopp, N., Illig, T., Preising, M. N., and Lorenz, B. (2006) Congenital cataract and macular hypoplasia in humans associated with a de novo mutation in CRYAA and compound heterozygous mutations in P, Graefes Arch. Clin. Exp. Ophthalmol., 244, 912-919, https://doi.org/10.1007/s00417-005-0234-x.

    Article  CAS  PubMed  Google Scholar 

  87. Hansen, L., Mikkelsen, A., Nurnberg, P., Nurnberg, G., Anjum, I., et al. (2009) Comprehensive mutational screening in a cohort of Danish families with hereditary congenital cataract, Invest. Ophthalmol. Vis. Sci., 50, 3291-3303, https://doi.org/10.1167/iovs.08-3149.

    Article  PubMed  Google Scholar 

  88. Laurie, K. J., Dave, A., Straga, T., Souzeau, E., Chataway, T., et al. (2013) Identification of a novel oligomerization disrupting mutation in CRYAlphaA associated with congenital cataract in a South Australian family, Hum. Mutat., 34, 435-438, https://doi.org/10.1002/humu.22260.

    Article  CAS  PubMed  Google Scholar 

  89. Mackay, D. S., Andley, U. P., and Shiels, A. (2003) Cell death triggered by a novel mutation in the alphaA-crystallin gene underlies autosomal dominant cataract linked to chromosome 21q, Eur. J. Hum. Genet., 11, 784-793, https://doi.org/10.1038/sj.ejhg.5201046.

    Article  CAS  PubMed  Google Scholar 

  90. Khan, A. O., Aldahmesh, M. A., and Meyer, B. (2007) Recessive congenital total cataract with microcornea and heterozygote carrier signs caused by a novel missense CRYAA mutation (R54C), Am. J. Ophthalmol., 144, 949-952, https://doi.org/10.1016/j.ajo.2007.08.005.

    Article  CAS  PubMed  Google Scholar 

  91. Su, D., Guo, Y., Li, Q., Guan, L., Zhu, S., et al. (2012) A novel mutation in CRYAA is associated with autosomal dominant suture cataracts in a Chinese family, Mol. Vis., 18, 3057-3063.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Yang, Z., Su, D., Li, Q., Ma, Z., Yang, F., et al. (2013) A R54L mutation of CRYAA associated with autosomal dominant nuclear cataracts in a Chinese family, Curr. Eye Res., 38, 1221-1228, https://doi.org/10.3109/02713683.2013.811260.

    Article  CAS  PubMed  Google Scholar 

  93. Patel, R., Zenith, R. K., Chandra, A., and Ali, A. (2017) Novel mutations in the crystallin gene in age-related cataract patients from a North Indian population, Mol. Syndromol., 8, 179-186, https://doi.org/10.1159/000471992.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Bhagyalaxmi, S. G., Srinivas, P., Barton, K. A., Kumar, K. R., Vidyavathi, M., et al. (2009) A novel mutation (F71L) in alphaA-crystallin with defective chaperone-like function associated with age-related cataract, Biochim. Biophys. Acta, 1792, 974-981, https://doi.org/10.1016/j.bbadis.2009.06.011.

    Article  CAS  PubMed  Google Scholar 

  95. Santhiya, S. T., Soker, T., Klopp, N., Illig, T., Prakash, M. V., et al. (2006) Identification of a novel, putative cataract-causing allele in CRYAA (G98R) in an Indian family, Mol. Vis., 12, 768-773.

    CAS  PubMed  Google Scholar 

  96. Vanita, V., Singh, J. R., Hejtmancik, J. F., Nuernberg, P., Hennies, H. C., et al. (2006) A novel fan-shaped cataract-microcornea syndrome caused by a mutation of CRYAA in an Indian family, Mol. Vis., 12, 518-522.

    CAS  PubMed  Google Scholar 

  97. Li, F. F., Yang, M., Ma, X., Zhang, Q., Zhang, M., et al. (2010) Autosomal dominant congenital nuclear cataracts caused by a CRYAA gene mutation, Curr. Eye Res., 35, 492-498, https://doi.org/10.3109/02713681003624901.

    Article  CAS  PubMed  Google Scholar 

  98. Gu, F., Luo, W., Li, X., Wang, Z., Lu, S., et al. (2008) A novel mutation in AlphaA-crystallin (CRYAA) caused autosomal dominant congenital cataract in a large Chinese family, Hum. Mutat., 29, 769, https://doi.org/10.1002/humu.20724.

    Article  PubMed  Google Scholar 

  99. Richter, L., Flodman, P., Barria von-Bischhoffshausen, F., Burch, D., Brown, S., et al. (2008) Clinical variability of autosomal dominant cataract, microcornea and corneal opacity and novel mutation in the alpha A crystallin gene (CRYAA), Am. J. Med. Genet. A, 146A, 833-842, https://doi.org/10.1002/ajmg.a.32236.

    Article  CAS  PubMed  Google Scholar 

  100. Li, L., Fan, D. B., Zhao, Y. T., Li, Y., Kong, D. Q., et al. (2017) Two novel mutations identified in ADCC families impair crystallin protein distribution and induce apoptosis in human lens epithelial cells, Sci. Rep., 7, 17848, https://doi.org/10.1038/s41598-017-18222-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Sun, W., Xiao, X., Li, S., Guo, X., and Zhang, Q. (2011) Mutation analysis of 12 genes in Chinese families with congenital cataracts, Mol. Vis., 17, 2197-2206.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Kong, X. D., Liu, N., Shi, H. R., Dong, J. M., Zhao, Z. H., et al. (2015) A novel 3-base pair deletion of the CRYAA gene identified in a large Chinese pedigree featuring autosomal dominant congenital perinuclear cataract, Genet. Mol. Res., 14, 426-432, https://doi.org/10.4238/2015.

    Article  PubMed  Google Scholar 

  103. Berry, V., Ionides, A., Pontikos, N., Georgiou, M., Yu, J., et al. (2020) The genetic landscape of crystallins in congenital cataract, Orphanet. J. Rare Dis., 15, 333, https://doi.org/10.1186/s13023-020-01613-3.

    Article  PubMed  PubMed Central  Google Scholar 

  104. Chen, Q., Ma, J., Yan, M., Mothobi, M. E., Liu, Y., et al. (2009) A novel mutation in CRYAB associated with autosomal dominant congenital nuclear cataract in a Chinese family, Mol. Vis., 15, 1359-1365.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Jiao, X., Khan, S. Y., Irum, B., Khan, A. O., Wang, Q., et al. (2015) Missense mutations in CRYAB are liable for recessive congenital cataracts, PLoS One, 10, e0137973, https://doi.org/10.1371/journal.pone.0137973.

    Article  CAS  PubMed  Google Scholar 

  106. Liu, M., Ke, T., Wang, Z., Yang, Q., Chang, W., et al. (2006) Identification of a CRYAB mutation associated with autosomal dominant posterior polar cataract in a Chinese family, Invest. Ophthalmol. Vis. Sci., 47, 3461-3466, https://doi.org/10.1167/iovs.05-1438.

    Article  PubMed  Google Scholar 

  107. Xia, X. Y., Wu, Q. Y., An, L. M., Li, W. W., Li, N., et al. (2014) A novel P20R mutation in the alpha-B crystallin gene causes autosomal dominant congenital posterior polar cataracts in a Chinese family, BMC Ophthalmol., 14, 108, https://doi.org/10.1186/1471-2415-14-108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Del Bigio, M. R., Chudley, A. E., Sarnat, H. B., Campbell, C., Goobie, S., et al. (2011) Infantile muscular dystrophy in Canadian aboriginals is an alphaB-crystallinopathy, Ann. Neurol., 69, 866-871, https://doi.org/10.1002/ana.22331.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Khan, A. O., Abu Safieh, L., and Alkuraya, F. S. (2010) Later retinal degeneration following childhood surgical aphakia in a family with recessive CRYAB mutation (p.R56W), Ophthalmic Genet., 31, 30-36, https://doi.org/10.3109/13816810903452047.

    Article  CAS  PubMed  Google Scholar 

  110. Fichna, J. P., Potulska-Chromik, A., Miszta, P., Redowicz, M. J., Kaminska, A. M., et al. (2017) A novel dominant D109A CRYAB mutation in a family with myofibrillar myopathy affects alphaB-crystallin structure, BBA Clin., 7, 1-7, https://doi.org/10.1016/j.bbacli.2016.11.004.

    Article  PubMed  Google Scholar 

  111. Brodehl, A., Gaertner-Rommel, A., Klauke, B., Grewe, S. A., Schirmer, I., et al. (2017) The novel alphaB-crystallin (CRYAB) mutation p.D109G causes restrictive cardiomyopathy, Hum. Mutat., 38, 947-952, https://doi.org/10.1002/humu.23248.

    Article  CAS  PubMed  Google Scholar 

  112. Sacconi, S., Feasson, L., Antoine, J. C., Pecheux, C., Bernard, R., et al. (2012) A novel CRYAB mutation resulting in multisystemic disease, Neuromuscul. Disord., 22, 66-72, https://doi.org/10.1016/j.nmd.2011.07.004.

    Article  PubMed  Google Scholar 

  113. Vicart, P., Caron, A., Guicheney, P., Li, Z., Prevost, M. C., et al. (1998) A missense mutation in the alphaB-crystallin chaperone gene causes a desmin-related myopathy, Nat. Genet., 20, 92-95, https://doi.org/10.1038/1765.

    Article  CAS  PubMed  Google Scholar 

  114. Liu, Y., Zhang, X., Luo, L., Wu, M., Zeng, R., et al. (2006) A novel alphaB-crystallin mutation associated with autosomal dominant congenital lamellar cataract, Invest. Ophthalmol. Vis. Sci., 47, 1069-1075, https://doi.org/10.1167/iovs.05-1004.

    Article  PubMed  Google Scholar 

  115. Selcen, D., and Engel, A. G. (2003) Myofibrillar myopathy caused by novel dominant negative alpha B-crystallin mutations, Ann. Neurol., 54, 804-810, https://doi.org/10.1002/ana.10767.

    Article  CAS  PubMed  Google Scholar 

  116. Reilich, P., Schoser, B., Schramm, N., Krause, S., Schessl, J., et al. (2010) The p. G154S mutation of the alpha-B crystallin gene (CRYAB) causes late-onset distal myopathy, Neuromuscul. Disord., 20, 255-259, https://doi.org/10.1016/j.nmd.2010.01.012.

    Article  PubMed  Google Scholar 

  117. Inagaki, N., Hayashi, T., Arimura, T., Koga, Y., Takahashi, M., et al. (2006) Alpha B-crystallin mutation in dilated cardiomyopathy, Biochem. Biophys. Res. Commun., 342, 379-386, https://doi.org/10.1016/j.bbrc.2006.01.154.

    Article  CAS  PubMed  Google Scholar 

  118. Berry, V., Francis, P., Reddy, M. A., Collyer, D., Vithana, E., et al. (2001) Alpha-B crystallin gene (CRYAB) mutation causes dominant congenital posterior polar cataract in humans, Am. J. Hum. Genet., 69, 1141-1145, https://doi.org/10.1086/324158.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Forrest, K. M., Al-Sarraj, S., Sewry, C., Buk, S., Tan, S. V., et al. (2011) Infantile onset myofibrillar myopathy due to recessive CRYAB mutations, Neuromuscul. Disord., 21, 37-40, https://doi.org/10.1016/j.nmd.2010.11.003.

    Article  PubMed  Google Scholar 

  120. Marcos, A. T., Amoros, D., Munoz-Cabello, B., Galan, F., Rivas Infante, E., et al. (2020) A novel dominant mutation in CRYAB gene leading to a severe phenotype with childhood onset, Mol. Genet. Genomic Med., 8, e1290, https://doi.org/10.1002/mgg3.1290.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Van der Smagt, J. J., Vink, A., Kirkels, J. H., Nelen, M., ter Heide, H., et al. (2014) Congenital posterior pole cataract and adult onset dilating cardiomyopathy: Expanding the phenotype of alphaB-crystallinopathies, Clin. Genet., 85, 381-385, https://doi.org/10.1111/cge.12169.

    Article  CAS  PubMed  Google Scholar 

  122. Yu, Y., Xu, J., Qiao, Y., Li, J., and Yao, K. (2021) A new heterozygous mutation in the stop codon of CRYAB (p. X176Y) is liable for congenital posterior pole cataract in a Chinese family, Ophthalmic Genet., 42, 139-143, https://doi.org/10.1080/13816810.2020.1855665.

    Article  CAS  PubMed  Google Scholar 

  123. Muranova, L. K., Strelkov, S. V., and Gusev, N. B. (2020) Effect of cataract-associated mutations in the N-terminal domain of alphaB-crystallin (HspB5), Exp. Eye Res., 197, 108091, https://doi.org/10.1016/j.exer.2020.108091.

    Article  CAS  PubMed  Google Scholar 

  124. Cobb, B. A., and Petrash, J. M. (2000) Structural and functional changes in the alpha A-crystallin R116C mutant in hereditary cataracts, Biochemistry, 39, 15791-15798, https://doi.org/10.1021/bi001453j.

    Article  CAS  PubMed  Google Scholar 

  125. Kumar, L. V., Ramakrishna, T., and Rao, C. M. (1999) Structural and functional consequences of the mutation of a conserved arginine residue in alphaA and alphaB crystallins, J. Biol. Chem., 274, 24137-24141, https://doi.org/10.1074/jbc.274.34.24137.

    Article  CAS  PubMed  Google Scholar 

  126. Singh, D., Raman, B., Ramakrishna, T., and Rao, Ch. M. (2006) The cataract-causing mutation G98R in human alphaA-crystallin leads to folding defects and loss of chaperone activity, Mol. Vis., 12, 1372-1379.

    CAS  PubMed  Google Scholar 

  127. Bova, M. P., Yaron, O., Huang, Q., Ding, L., Haley, D. A., et al. (1999) Mutation R120G in alphaB-crystallin, which is linked to a desmin-related myopathy, results in an irregular structure and defective chaperone-like function, Proc. Natl. Acad. Sci. USA, 96, 6137-6142, https://doi.org/10.1073/pnas.96.11.6137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Perng, M. D., Wen, S. F., van IJssel, P., Prescott, A. R., and Quinlan, R. A. (2004) Desmin aggregate formation by R120G alphaB-crystallin is caused by altered filament interactions and is dependent upon network status in cells, Mol. Biol. Cell, 15, 2335-2346, https://doi.org/10.1091/mbc.e03-12-0893.

    Article  CAS  PubMed  Google Scholar 

  129. Ghahramani, M., Yousefi, R., Krivandin, A., Muranov, K., Kurganov, B., et al. (2020) Structural and functional characterization of D109H and R69C mutant versions of human alphaB-crystallin: The biochemical pathomechanism underlying cataract and myopathy development, Int. J. Biol. Macromol., 146, 1142-1160, https://doi.org/10.1016/j.ijbiomac.2019.09.239.

    Article  CAS  PubMed  Google Scholar 

  130. Clark, A. R., Lubsen, N. H., and Slingsby, C. (2012) sHSP in the eye lens: Crystallin mutations, cataract and proteostasis, Int. J. Biochem. Cell Biol., 44, 1687-1697, https://doi.org/10.1016/j.biocel.2012.02.015.

    Article  CAS  PubMed  Google Scholar 

  131. Gerasimovich, E. S., Strelkov, S. V., and Gusev, N. B. (2017) Some properties of three alphaB-crystallin mutants carrying point substitutions in the C-terminal domain and associated with congenital diseases, Biochimie, 142, 168-178, https://doi.org/10.1016/j.biochi.2017.09.008.

    Article  CAS  PubMed  Google Scholar 

  132. Raju, I., and Abraham, E. C. (2011) Congenital cataract causing mutants of alphaA-crystallin/sHSP form aggregates and aggresomes degraded through ubiquitin–proteasome pathway, PLoS One, 6, e28085, https://doi.org/10.1371/journal.pone.0028085.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Ahsan, S. M., Bakthisaran, R., Tangirala, R., and Rao, C. M. (2021) Nucleosomal association and altered interactome underlie the mechanism of cataract caused by the R54C mutation of alphaA-crystallin, Biochim. Biophys. Acta Gen. Subj., 1865, 129846, https://doi.org/10.1016/j.bbagen.2021.129846.

    Article  CAS  PubMed  Google Scholar 

  134. Gong, B., Zhang, L. Y., Pang, C. P., Lam, D. S., and Yam, G. H. (2009) Trimethylamine N-oxide alleviates the severe aggregation and ER stress caused by G98R alphaA-crystallin, Mol. Vis., 15, 2829-2840.

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Raju, I., and Abraham, E. C. (2013) Mutants of human alphaB-crystallin cause enhanced protein aggregation and apoptosis in mammalian cells: Influence of co-expression of HspB1, Biochem. Biophys. Res. Commun., 430, 107-112, https://doi.org/10.1016/j.bbrc.2012.11.051.

    Article  CAS  PubMed  Google Scholar 

  136. Chavez Zobel, A. T., Loranger, A., Marceau, N., Theriault, J. R., Lambert, H., et al. (2003) Distinct chaperone mechanisms can delay the formation of aggresomes by the myopathy-causing R120G alphaB-crystallin mutant, Hum. Mol. Genet., 12, 1609-1620, https://doi.org/10.1093/hmg/ddg173.

    Article  CAS  PubMed  Google Scholar 

  137. Sanbe, A., Osinska, H., Saffitz, J. E., Glabe, C. G., Kayed, R., et al. (2004) Desmin-related cardiomyopathy in transgenic mice: a cardiac amyloidosis, Proc. Natl. Acad. Sci. USA, 101, 10132-10136, https://doi.org/10.1073/pnas.0401900101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Hayes, V. H., Devlin, G., and Quinlan, R. A. (2008) Truncation of alphaB-crystallin by the myopathy-causing Q151X mutation significantly destabilizes the protein leading to aggregate formation in transfected cells, J. Biol. Chem., 283, 10500-10512, https://doi.org/10.1074/jbc.M706453200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Mitzelfelt, K. A., Limphong, P., Choi, M. J., Kondrat, F. D., Lai, S., et al. (2016) The human 343delT HSPB5 chaperone associated with early-onset skeletal myopathy causes defects in protein solubility, J. Biol. Chem., 291, 14939-14953, https://doi.org/10.1074/jbc.M116.730481.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Zhang, H., Rajasekaran, N. S., Orosz, A., Xiao, X., Rechsteiner, M., et al. (2010) Selective degradation of aggregate-prone CryAB mutants by HSPB1 is mediated by ubiquitin-proteasome pathways, J. Mol. Cell. Cardiol., 49, 918-930, https://doi.org/10.1016/j.yjmcc.2010.09.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Andley, U. P., Hamilton, P. D., and Ravi, N. (2008) Mechanism of insolubilization by a single-point mutation in alphaA-crystallin linked with hereditary human cataracts, Biochemistry, 47, 9697-9706, https://doi.org/10.1021/bi800594t.

    Article  CAS  PubMed  Google Scholar 

  142. Kore, R., Hedges, R. A., Oonthonpan, L., Santhoshkumar, P., Sharma, K. K., et al. (2012) Quaternary structural parameters of the congenital cataract causing mutants of alphaA-crystallin, Mol. Cell Biochem., 362, 93-102, https://doi.org/10.1007/s11010-011-1131-8.

    Article  CAS  PubMed  Google Scholar 

  143. Khoshaman, K., Yousefi, R., Tamaddon, A. M., Abolmaali, S. S., Oryan, A., et al. (2017) The impact of different mutations at Arg54 on structure, chaperone-like activity and oligomerization state of human alphaA-crystallin: The pathomechanism underlying congenital cataract-causing mutations R54L, R54P and R54C, Biochim. Biophys. Acta Proteins Proteom., 1865, 604-618, https://doi.org/10.1016/j.bbapap.2017.02.003.

    Article  CAS  PubMed  Google Scholar 

  144. Murugesan, R., Santhoshkumar, P., and Sharma, K. K. (2007) Cataract-causing alphaAG98R mutant shows substrate-dependent chaperone activity, Mol. Vis., 13, 2301-2309.

    PubMed  Google Scholar 

  145. Singh, D., Tangirala, R., Bakthisaran, R., and Chintalagiri, M. R. (2009) Synergistic effects of metal ion and the pre-senile cataract-causing G98R alphaA-crystallin: Self-aggregation propensities and chaperone activity, Mol. Vis., 15, 2050-2060.

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Wang, X., Osinska, H., Klevitsky, R., Gerdes, A. M., Nieman, M., et al. (2001) Expression of R120G-alphaB-crystallin causes aberrant desmin and alphaB-crystallin aggregation and cardiomyopathy in mice, Circ. Res., 89, 84-91, https://doi.org/10.1161/hh1301.092688.

    Article  CAS  PubMed  Google Scholar 

  147. Meehan, S., Berry, Y., Luisi, B., Dobson, C. M., Carver, J. A., et al. (2004) Amyloid fibril formation by lens crystallin proteins and its implications for cataract formation, J. Biol. Chem., 279, 3413-3419, https://doi.org/10.1074/jbc.M308203200.

    Article  CAS  PubMed  Google Scholar 

  148. Lee, C. F. (2009) Self-assembly of protein amyloids: A competition between amorphous and ordered aggregation, Phys. Rev. E Stat. Nonlin. Soft Matter Phys., 80, 031922, https://doi.org/10.1103/PhysRevE.80.031922.

    Article  CAS  PubMed  Google Scholar 

  149. Sandilands, A., Hutcheson, A. M., Long, H. A., Prescott, A. R., Vrensen, G., et al. (2002) Altered aggregation properties of mutant gamma-crystallins cause inherited cataract, EMBO J., 21, 6005-6014, https://doi.org/10.1093/emboj/cdf609.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Meehan, S., Knowles, T. P., Baldwin, A. J., Smith, J. F., Squires, A. M., et al. (2007) Characterisation of amyloid fibril formation by small heat-shock chaperone proteins human alphaA-, alphaB- and R120G alphaB-crystallins, J. Mol. Biol., 372, 470-484, https://doi.org/10.1016/j.jmb.2007.06.060.

    Article  CAS  PubMed  Google Scholar 

  151. Makley, L. N., McMenimen, K. A., DeVree, B. T., Goldman, J. W., McGlasson, B. N., et al. (2015) Pharmacological chaperone for alpha-crystallin partially restores transparency in cataract models, Science, 350, 674-677, https://doi.org/10.1126/science.aac9145.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Zhao, L., Chen, X. J., Zhu, J., Xi, Y. B., Yang, X., et al. (2015) Lanosterol reverses protein aggregation in cataracts, Nature, 523, 607-611, https://doi.org/10.1038/nature14650.

    Article  CAS  PubMed  Google Scholar 

  153. Raju, M., Santhoshkumar, P., and Sharma, K. (2016) Alpha-crystallin-derived peptides as therapeutic chaperones, Biochim. Biophys. Acta, 1860, 246-251, https://doi.org/10.1016/j.bbagen.2015.06.010.

    Article  CAS  PubMed  Google Scholar 

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  1. Centre for Cellular and Molecular Biology (CCMB), Council of Scientific and Industrial Research (CSIR), Uppal Road, 500007, Hyderabad, India

    Prashanth Budnar, Ramakrishna Tangirala, Raman Bakthisaran & Ch. Mohan Rao

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The article is published as a part of the Special Issue “Protein Misfolding and Aggregation in Cataract Disorders” (Vol. 87, No. 2).

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Budnar, P., Tangirala, R., Bakthisaran, R. et al. Protein Aggregation and Cataract: Role of Age-Related Modifications and Mutations in α-Crystallins. Biochemistry Moscow 87, 225–241 (2022). https://doi.org/10.1134/S000629792203004X

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  • DOI: https://doi.org/10.1134/S000629792203004X

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