Structure of the crystallins


The lens is formed from two protein superfamilies, the α- and βγ-crystallins. Representative three-dimensional structures show they both have a basic 2-β-sheet domain fold, with the βγ-domain being made from two intercalating Greek keys. X-ray structures of monomeric γ-crystallins and simple oligomeric β-crystallins show how multiple gene duplications can give rise to highly symmetrical assemblies based on paired domains. These protein folds have been engineered by directed mutagenesis to investigate the roles of the critical region in domain pairing and assembly. Inherited human cataracts have been described that are associated with representatives of each of the crystallin protein families. Mutations to certain β- and γ-crystallin genes cause expression of truncated polypeptides that would not be expected to fold properly; instead they would randomly aggregate causing light scattering. As crystallin proteins are not renewed, age-related cataract is a gradual accumulation of small changes to preexisting normal proteins. The precise sites of post-translational modifications are now being mapped to the various crystalline.


  1. 1

    Wright AF . A searchlight through the fog. Nature Genet 1997;17:132–4.

  2. 2

    Harding J . Cataract: biochemistry, epidemiology and pharmacology. London: Chapman & Hall, 1991.

  3. 3

    Delaye M, Tardieu A . Short-range order of crystallin proteins accounts for eye lens transparency. Nature 1983;302:415–7.

  4. 4

    Benedek GB . Cataract as a protein condensation disease. The Proctor lecture. Invest Ophthalmol Vis Sci 1997;38:1911–21.

  5. 5

    Slingsby, C, Norledge B, Simpson, A, Bateman OA, Wright G, Driessen HPC, et al. X-ray diffraction and structure of crystallins. Prog Ret Eye Res 1997;16:3–29.

  6. 6

    Caspers G-J, Leunissen JAM, de Jong WW . The expanding small heat shock protein family, and structure predictions of the conserved ‘α-crystallin domain’. J Mol Evol 1995;40:238–48.

  7. 7

    Kim KK, Kim R, Kim S-H . Crystal structure of a small heat-shock protein. Nature 1998;394:595–9.

  8. 8

    Lubsen NH, Aarts HJM, Schoenmakers JGG The evolution of lenticular proteins: the β- and γ-crystallin super gene family. Prog Biophys Mol Biol 1998;51:47–56.

  9. 9

    Mayr E-M, Jaenicke R, Glockshuber R . The domains in 7B-crystallin: identical fold - different stabilities. J Mol Biol 1997;269:260–9.

  10. 10

    Norledge BV, Mayr E-M, Glockshuber R, Bateman OA, Slingsby C, Jaenicke R, et al. The X-ray structures of two mutant crystallin domains shed light on the evolution of multi-domain proteins. Nature Struct Biol 1996;3:267–74.

  11. 11

    Strivastava OP, Strivastava K, Silney C . Covalent modification at the C-terminal end of a 9 kDa γD-crystallin fragment in human lenses. Exp Eye Res 1994;58:595–604.

  12. 12

    Meakin SO, Du RP, Tsui L-C, Breitman ML . 7-crystallins of the human eye lens: expression analysis of five members of the gene family. Mol Cell Biol 1987;7:2671–9.

  13. 13

    Broide ML, Berland CR, Pande J, Ogun OO, Benedek GB . Binary-liquid phase separation of lens protein solutions. Proc Natl Acad Sci USA 1991;88:5660–4.

  14. 14

    Norledge BV, Hay RE, Bateman OA, Slingsby C, Driessen HPC . Towards a molecular understanding of phase separation in the lens: a comparison of the X-ray structures of two high Tc γ-crystallins, γE and γF, with two low Tc γ-crystallins, γB and 7D. Exp Eye Res 1997;65:609–30.

  15. 15

    de Jong WW, Lubsen NH, Kraft HJ . Molecular evolution of the eye lens. Prog Ret Eye Res 1994;13:391–442.

  16. 16

    Palme S, Jaenicke R, Slingsby C . Unusual domain pairing in a mutant of bovine lens γB-crystallin. J Mol Biol 1998;279:1053–9.

  17. 17

    Basak AK, Kroone RC, Lubsen NH, Naylor CE, Jaenicke R, Slingsby C . The C-terminal domains of γS-crystallin pair about a distorted twofold axis. Protein Eng 1998;11:337–44.

  18. 18

    Palme S, Jaenicke R, Slingsby C . X-ray structures of three interface mutants of γB-crystallin from bovine eye lens. Protein Sci 1998;7:611–8.

  19. 19

    Bax B, Lapatto R, Nalini V, Driessen H, Lindley PF, Mahadevan D, et al. X-ray analysis of βB2-crystallin and evolution of oligomeric lens proteins. Nature 1990;347:776–80.

  20. 20

    Mayr E-M, Jaenicke R, Glockshuber R . Domain interactions and connecting peptides in lens crystalline. J Mol Biol 1994;235:84–8.

  21. 21

    Trinkl S, Glockshuber R, Jaenicke R . Dimerization of βB2-crystallin: the role of the linker peptide and the N- and C-terminal extensions. Protein Sci 1994;3:1392–400.

  22. 22

    Hope JN, Chen H-C, Hejtmancik JF . Aggregation of βA3-crystallin is independent of the specific sequence of the domain connecting peptide. J Biol Chem 1994;269:21141–5.

  23. 23

    Norledge BV, Trinkl S, Jaenicke R, Slingsby C . The X-ray structure of a mutant eye lens βB2-crystallin with truncated sequence extensions. Protein Sci 1997;6:1612–20.

  24. 24

    Wieligmann K, Norledge B, Jaenicke R, Mayr E-M . Eye lens βB2-crystallin: circular permutation does not influence the oligomerization state but enhances the conformational stability. J Mol Biol 1998;280:721–9.

  25. 25

    Wright G, Basak AK, Wieligmann K, Mayr E-M, Slingsby C . Circular permutation of βB2 changes the hierarchy of domain assembly. Protein Sci 1998;7:1280–5.

  26. 26

    Slingsby C, Bateman OA . Quaternary interactions in eye lens β-crystallins: basic and acidic subunits of β-crystallins favour heterologous association. Biochemistry 1990;29:6592–9.

  27. 27

    Ma Z, Hanson SRA, Lampi KJ, David LL, Smith DL, Smith JB . Age-related changes in human lens crystallins identified by HPLC and mass spectrometry. Exp Eye Res 1998;67:21–30.

  28. 28

    Lampi KJ, Ma Z, Hanson SRA, Azuma M, Shih M, Shearer TR, et al. Age-related changes in human lens crystallins identified by two-dimensional electrophoresis and mass spectrometry. Exp Eye Res 1998;67:31–43.

  29. 29

    Ajaz MS, Ma Z, Smith DL, Smith JB . Size of human lens β-crystallin aggregates are distinguished by N-terminal truncation of βBl. J Biol Chem 1997;272:11250–5.

  30. 30

    Nalini V, Bax B, Driessen H, Moss DS, Lindley PF, Slingsby C . Close packing of an oligomeric eye lens β-crystallin induces loss of symmetry and ordering of sequence extensions. J Mol Biol 1994;236:1250–8.

  31. 31

    Wistow G . Molecular biology and evolution of crystallins: gene recruitment and multifunctional proteins in the eye lens. Austin/New York: RG Landes/Springer, 1995.

  32. 32

    Clout NJ, Slingsby C, Wistow GJ . An eye on crystallins. Nature Struct Biol 1997;4:685.

  33. 33

    Ray ME, Wistow G, Su YA, Meltzer PS, Trent JM . AIM1, a novel non-lens member of the β7-crystallin superfamily, is associated with the control of tumorigenicity in human malignant melanoma. Proc Natl Acad Sci USA 1997;94:3229–34.

  34. 34

    Sinha D, Esumi N, Jaworski C, Kozak CA, Pierce E, Wistow G . Cloning and mapping the mouse Crygs gene and non-lens expression of γS-crystallin. 1998.

  35. 35

    Horwitz J . Alpha-crystallin can function as a molecular chaperone. Proc Natl Acad Sci USA 1992;89:10449–53.

  36. 36

    Mornon JP, Halaby D, Malfois M, Durand P, Callebaut I, Tardieu A . Alpha-crystallin C-terminal domain: on the track of an Ig fold. Int J Biol Macromol 1998;22:219–27.

  37. 37

    Lee GJ, Roseman AM, Saibil HR, Vierling E . A small heat shock protein stably binds heat-denatured model substrates and can maintain substrate in a folding-competent state. EMBOJ 1997;16:659–71.

  38. 38

    Hetjmancik JF . The genetics of cataract: our vision becomes clearer. Am J Genet 1998;62:520–5.

  39. 39

    Brakenhoff RH, Henskens HAM, van Rossum MWPC, Lubsen NH, Schoenmakers JGG . Activation of the gammaE-crystallin pseudogene in the human hereditary Coppock-like cataract. Hum Mol Genet 1994;3:279–83.

  40. 40

    Litt M, Carrero-Valenzuela R, LaMorticella DM, Schultz DW, Mitchell TN, Kramer P, Maumenee IH . Autosomal dominant cerulean cataract is associated with a chain termination in the human β-crystallin gene CRYBB2. Hum Mol Genet 1997;6:665–8.

  41. 41

    Bateman OA, Slingsby C . Structural studies on βH-cry stallin from bovine eye lens. Exp Eye Res 1992;55:127–33.

  42. 42

    Litt M, Kramer P, LaMorticella DM, Murphey W, Lovrien EW, Weleber RG . Autosomal dominant congenital cataract associated with a missense mutation in the human alpha crystallin gene CRYAA. Hum Mol Genet 1998;7:471–4.

  43. 43

    Chambers C, Russell P . Deletion mutation in an eye lens β-crystallin. J Biol Chem 1991;266:6742–6.

  44. 44

    Russell P, Chambers C . Interaction of an altered β-crystallin with other proteins in the Philly mouse lens. Exp Eye Res 1990;50:683–7.

  45. 45

    Cartier M, Breitman ML, Tsui LC . A frameshift mutation in the γE-crystallin gene of the Elo mouse. Nature Genet 1992;2:42–5.

  46. 46

    Gong X, Li E, Klier G, Huang Q, Wu Y, Lei H, et al. Disruption of α3 connexin gene leads to proteolysis and cataractogenesis in mice. Cell 1997;91:833–43.

  47. 47

    Shiels A, Mackay D, Ionides A, Berry V, Moore A, Bhattacharya S . A missense mutation in the human connexin 50 gene (GJA8) underlines autosomal dominant ‘zonular pulverulent‘ cataract, on chromosome 1q. Am J Hum Genet 1998;62:526–32.

  48. 48

    Garland DL, Duglas-Tabor Y, Jimenez-Asensio J, Datiles MB, Magno B . The nucleus of the human lens: demonstration of a highly characteristic protein pattern by 2D electrophoresis and introduction of new method of lens dissection. Exp Eye Res 1996;62:285–91.

  49. 49

    Najmudin S, Nalini V, Driessen HPC, Slingsby C, Blundell TL, Moss DS, Lindley PF . Structure of the bovine eye lens protein γB(γII)-crystallin at 1.47Å. Acta Cryst 1993;D49:223–33.

  50. 50

    Takemoto LJ . Disulphide bond formation of cysteine-37 and cysteine-66 of βB2 crystallin during cataractogenesis of the human lens. Exp Eye Res 1997;64:609–14.

  51. 51

    Evans SV . SETOR: hardware lighted three-dimensional solid model representations of macromolecules. J Mol Graphics 1993;11:134–8.

Download references

Author information

Correspondence to Christine Slingsby.

Rights and permissions

Reprints and Permissions

About this article


  • Cataract
  • Crystallin
  • Domain fold
  • Evolution
  • Eye lens
  • Protein structure

Further reading