Zinc and Copper Ions Induce Aggregation of Human β-Crystallins

Abstract

Cataracts are defined as the clouding of the lens due to the formation of insoluble protein aggregates. Metal ions exposure has been recognized as a risk factor in the cataract formation process. The γ and β crystallins are members of a larger family and share several structural features. Several studies have shown that copper and zinc ions induce the formation of γ-crystallins aggregates. However, the interaction of metal ions with β-crystallins, some of the most abundant crystallins in the lens, has not been explored until now. Here, we evaluate the effect of Cu(II) and Zn(II) ions on the aggregation of HβA1, as a representative of the acidic form, and HβB2, as a representative of the basic β-crystallins. We used several biophysical techniques and computational methods to show that Cu(II) and Zn(II) induce aggregation following different pathways. Both metal ions destabilize the proteins and impact protein folding. Copper induced a small conformational change in HβA1, leading to high-molecular-weight light-scattering aggregates, while zinc is more aggressive towards HβB2 and induces a larger conformational change. Our work provides information on the mechanisms of metal-induced aggregation of β-crystallins.

A bibliometric and visualized analysis of the pathogenesis of cataracts from 1999 to 2023

“…In addition to genetic mutations, other causes of abnormal protein structures and functions can lead to cataracts. Zinc and copper ions induce aggregation of human β-crystalline protein [ 144 ]. High sugar levels induce glycosylation and crystal aggregation, which in turn, lead to diabetic cataracts [ 145 ].…”

Glycyl-l-histidyl-l-lysine prevents copper- and zinc-induced protein aggregation and central nervous system cell death in vitro

“… 12 , 18 Likewise, zinc is highly toxic in its free form and drives protein aggregation through similar mechanisms by cysteine and histidine bond formation and aggregation. 86 , 128 …”

Stabilization challenges and aggregation in protein-based therapeutics in the pharmaceutical industry

“…Overall, understanding the precise impact of cations on protein aggregation remains a challenge, and further research is needed to establish a consensus. 37,111,113,114…”

“…Overall, understanding the precise impact of cations on protein aggregation remains a challenge, and further research is needed to establish a consensus. 37,111,113,114 Chemical modications, such as deamidation and oxidation, can have a signicant impact on the stability of proteinbased therapeutics, including antibodies. Deamidation involves the conversion of asparagine to aspartic acid or isoaspartic acid, while oxidation involves the addition of oxygen or reactive oxygen species to amino acid residues.…”