Structural and functional characterization of D109H and R69C mutant versions of human αB-crystallin: The biochemical pathomechanism underlying cataract and myopathy development

Int J Biol Macromol. 2020 Mar 1;146:1142-1160. doi: 10.1016/j.ijbiomac.2019.09.239. Epub 2019 Oct 31.


In human αB-crystallin (αB-Cry), the highly conserved residues arginine 69 (R69) and aspartate 109 (D109) are located within a critical motif of α-crystallin domain (ACD), contributing to the subunit interactions and oligomeric assembly. Recently, two missense mutations (R69C and D109H) in human αB-Cry have been reported to cause congenital cataract and myopathy disorders. We used various spectroscopic techniques, dynamic light scattering (DLS), small-angle X-ray scattering (SAXS), gel electrophoresis and transmission electron microscopy (TEM) to show how these mutations cause significant changes in structure, amyloidogenic feature and biological function of human αB-Cry. These pathogenic mutations resulted in the important alterations of the secondary, tertiary and oligomeric (quaternary) structures of human αB-Cry. The missense mutations were also capable to significantly increase the amyloidogenic propensity of human αB-Cry and to diminish the chaperone-like activity of this protein. The above mentioned changes were observed more noticeably after D109H mutation. The detrimental effects of D109H mutation may be due to the loss of salt bridge with R120 in the dimeric interface, flagging the anti-aggregation ability of αB-Cry chaperone. In conclusion, the R69C and D109H mutations displayed a significant damaging effect on the structure and chaperone function of human αB-Cry which could be considered as their biochemical pathomechanisms in development of congenital cataract and myopathy disorders.

Keywords: Amyloid fibrils; Chaperone function; Congenital cataract; Human αB-crystallin; Structure.

MeSH terms

  • Amyloid / metabolism
  • Animals
  • Cataract / genetics*
  • Cataract / pathology*
  • Cattle
  • Circular Dichroism
  • Escherichia coli / physiology
  • Hot Temperature
  • Humans
  • Molecular Chaperones / metabolism
  • Muscular Diseases / genetics*
  • Muscular Diseases / pathology*
  • Mutant Proteins / chemistry
  • Mutant Proteins / metabolism
  • Mutation / genetics*
  • Protein Denaturation
  • Protein Stability
  • Protein Structure, Secondary
  • Proteolysis
  • Scattering, Small Angle
  • Spectrometry, Fluorescence
  • Spectroscopy, Fourier Transform Infrared
  • Spectrum Analysis, Raman
  • X-Ray Diffraction
  • alpha-Crystallin B Chain / chemistry*
  • alpha-Crystallin B Chain / genetics*


  • Amyloid
  • CRYAB protein, human
  • Molecular Chaperones
  • Mutant Proteins
  • alpha-Crystallin B Chain