The alpha-, beta- and gamma-crystallins are the major protein components of the vertebrate eye lens, alpha-crystallin as a molecular chaperone as well as a structural protein, beta- and gamma-crystallins as structural proteins. For the lens to be able to retain life-long transparency in the absence of protein turnover, the crystallins must meet not only the requirement of solubility associated with high cellular concentration but that of longevity as well. For proteins, longevity is commonly assumed to be correlated with long-term retention of native structure, which in turn can be due to inherent thermodynamic stability, efficient capture and refolding of non-native protein by chaperones, or a combination of both. Understanding how the specific interactions that confer intrinsic stability of the protein fold are combined with the stabilizing effect of protein assembly, and how the non-specific interactions and associations of the assemblies enable the generation of highly concentrated solutions, is thus of importance to understand the loss of transparency of the lens with age. Post-translational modification can have a major effect on protein stability but an emerging theme of the few studies of the effect of post-translational modification of the crystallins is one of solubility and assembly. Here we review the structure, assembly, interactions, stability and post-translational modifications of the crystallins, not only in isolation but also as part of a multi-component system. The available data are discussed in the context of the establishment, the maintenance and finally, with age, the loss of transparency of the lens. Understanding the structural basis of protein stability and interactions in the healthy eye lens is the route to solve the enormous medical and economical problem of cataract.

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Ageing and vision: structure, stability and function of lens crystallins

3D domain swapping is a mechanism for forming oligomeric proteins from their monomers. In 3D domain swapping, one domain of a monomeric protein is replaced by the same domain from an identical protein chain. The result is an intertwined dimer or higher oligomer, with one domain of each subunit replaced by the identical domain from another subunit. The swapped "domain" can be as large as an entire tertiary globular domain, or as small as an alpha-helix or a strand of a beta-sheet. Examples of 3D domain swapping are reviewed that suggest domain swapping can serve as a mechanism for functional interconversion between monomers and oligomers, and that domain swapping may serve as a mechanism for evolution of some oligomeric proteins. Domain-swapped proteins present examples of a single protein chain folding into two distinct structures.

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3D domain swapping: A mechanism for oligomer assembly

Improvements in protein secondary structure prediction by an enhanced neural network

The acquisition of the native three-dimensional structure of proteins consists of sequential folding reactions with well-populated and well-defined structural intermediates. For small proteins successive stages in the folding have been resolved kinetically; these suggest that H-bonded elements of secondary structure are formed first, followed by folding steps to generate the complete tertiary structure.

Folding and association of proteins

Prediction of the tertiary structures of proteins may be carried out using a knowledge-based approach. This depends on identification of analogies in secondary structures, motifs, domains or ligand interactions between a protein to be modelled and those of known three-dimensional structures. Such techniques are of value in prediction of receptor structures to aid the design of drugs, herbicides or pesticides, antigens in vaccine design, and novel molecules in protein engineering.

Knowledge-based prediction of protein structures and the design of novel molecules.

X-ray analysis of the eye lens protein γ-II crystallin at 1·9 Å resolution

The Gram-negative bacterium Myxococcus xanthus has a complex life cycle1 during which large amounts of a protein of relative molecular mass (Mr) 19,000, known as protein S, are assembled into a spore surface coat by a process that specifically requires calcium ions2,3. The gene for protein S has been cloned and the DNA sequence shows that the gene product is composed of four internally repeated homologous sequences, each 40 amino acids long4. Although protein S resembles calmodulin both in its internally duplicated structure and its ability to bind calcium4, it apparently has a β-sheet secondary structure5 rather than the helix–loop–helix motifs that characterize the calmodulin family6–8. We now show that protein S has a striking homology with the β- and γ-crystallins of the vertebrate eye lens9–11 which are β-sheet proteins with internally duplicated structures. This implies that the β- and γ-crystallins evolved from already existing proteins, whose ancestors occurred in the prokaryotes. The biological function of protein S, as a closely packed, stable protein in a relatively dehydrated environment, has implications for the functions of crystalline, which are found closely packed in the lens fibre cells, where their stability is essential for maintenance of transparency.

Myxococcus xanthus spore coat protein S may have a similar structure to vertebrate lens beta gamma-crystallins.

Structural variation in mammalian γ-crystallins based on computer graphics analyses of human, rat and calf sequences 1. Core packing and surface properties

Lesley Summers

Papers

X-ray analysis of the eye lens protein γ-II crystallin at 1·9 Å resolution

Myxococcus xanthus spore coat protein S may have a similar structure to vertebrate lens beta gamma-crystallins.

Structural variation in mammalian γ-crystallins based on computer graphics analyses of human, rat and calf sequences 1. Core packing and surface properties