Gamma crystallins of the human eye lens

Background: Protein crystallins co me in three types (alpha, beta and gamma) and are found predominantly in the eye, and particularly in the lens, where they are packed into a compact, plastic, elastic, and transparent globule of proper refractive power range that aids in focusing incoming light on to the retina. Of these, the gamma-crystallins are found largely in the nuclear region of the lens at very high concentrations (>400 mg/ml). The connection between their structure and inter-molecular interactions and lens transparency is an issue of particular interest. Scope of review: We review the origin and phylogeny of the gamma crystallins, their special structure involving the use of Greek key supersecondary structural motif, and how they aid in offering the appropriate refractive index gradient, intermolecular short range attractive interactions (aiding in packing them into a transparent ball), the role that several of the constituent amino acid residues play in this process, the thermodynamic and kinetic stability and how even single point mutations can upset this delicate balance and lead to intermolecular aggregation, forming light-scattering particles which compromise transparency. We cite several examples of this, and illustrate this by cloning, expressing, isolating and comparing the properties of the mutant protein S39C of human gamma S-crystallin (associated with congenital cataract-microcornea), with those of the wild type molecule. In addition, we note that human gamma-crystallins are also present in other parts of the eye (e.g., retina), where their functions are yet to be understood. Major conclusions: There are several 'crucial' residues in and around the Greek key motifs which are essential to maintain the compact architecture of the crystallin molecules. We find that a mutation that replaces even one of these residues can lead to reduction in solubility, formation of light-scattering particles and loss of transparency in the molecular assembly. General significance: Such a molecular understanding of the process helps us construct the continuum of genotype-molecular structural phenotype-clinical (pathological) phenotype. This article is part of a Special Issue entitled Crystallin Biochemistry in Health and Disease. (C) 2016 Elsevier B.V. All rights reserved.