The Molecular Refractive Function of Lens γ-Crystallins

Abstract

γ-crystallins constitute the major protein component in the nucleus of the vertebrate eye lens. Present at very high concentrations, they exhibit extreme solubility and thermodynamic stability to prevent scattering of light and the formation of cataracts. However, functions beyond this structural role have remained mostly unclear. Here, we calculate molecular refractive index increments of crystallins. We show that all lens γ-crystallins have evolved a significantly elevated molecular refractive index increment, which is far above those of most proteins, including non-lens members of the βγ-crystallin family from different species. The same trait has evolved in parallel in crystallins of different phyla, including in the S-crystallins of cephalopods. A high refractive index increment can lower the crystallin concentration required to achieve a suitable refractive power of the lens, and thereby reduce their propensity to aggregate and form cataract. To produce a significant increase of the refractive index increment, a substantial global shift in the amino acid composition is required, which can naturally explain the highly unusual amino acid composition of γ-crystallins and their functional homologues. This function provides a new perspective for interpreting their molecular structure.

Inherited Congenital Cataract: A Guide to Suspect the Genetic Etiology in the Cataract Genesis

“…The Greek key motif is a structure of 4 β-sheets, folded in an antiparallel form that generates a folded compact domain [Richardson, 1977]. The values and gradients in the refractive index of lens proteins seem to be related to the Greek key motif [Zhao et al, 2011]. The central portion and the embryonic nuclear region of the lens are rich in β-and γ-crystallins.…”

Biophysical chemistry of the ageing eye lens

“…New cells develop from the epithelial layer via mitosis from which they then differentiate into fibre cells (Mochizuki and Masai 2014). As the new fibre cells develop, they express large amounts of crystallin proteins which are responsible for the refractive index and transparency of the lens (Aarts et al 1989;Zhao et al 2011). Newly differentiated fibre cells migrate towards the lens equator where they undergo denucleation and lose their internal sub-cellular structures (Bassnett 2002;Mochizuki and Masai 2014).…”

“…Lens crystallins show high refractive index increments compared to other proteins, due to large quantities of aromatic and sulphurous residues (Mahendiran et al 2014), and show strong absorbance of UV radiation (Chen et al 2009;Zhao et al 2011). In humans, the fibre cells exhibit a protein concentration of ∼320 mg ml −1 uniformly throughout the lens (Bloemendal et al 2004).…”

“…The βγ-crystallins are primarily responsible for the refractive index of the lens and tend to have an above average number of residues with high refractive index increments, i.e. aromatic (tyrosine, tryptophan and phenylalanine) and sulfur-containing (cysteine and methionine) amino acids (Mahendiran et al 2014;Zhao et al 2011). The highly soluble, highly stable, poly-dispersed nature of these proteins also minimises aggregation and crystallisation in the lens, ensuring high transparency (Piatigorsky et al 1994;Slingsby et al 2013).…”

NMR Studies of Eye Lens Crystallins

“…Other species have taxon-specific crystallins that have been recruited from diverse abundant, soluble proteins via gene sharing or duplication often followed by selection for increased refractivity of the protein itself. 13,14 This review will focus on the βγ -and α-crystallins because the majority of NMR studies reported so far have been on these types of proteins.…”