Structural Integrity of the Greek Key Motif in beta gamma-Crystallins Is Vital for Central Eye Lens Transparency

Background: We highlight an unrecognized physiological role for the Greek key motif, an evolutionarily conserved super-secondary structural topology of the beta gamma-crystallins. These proteins constitute the bulk of the human eye lens, packed at very high concentrations in a compact, globular, short-range order, generating transparency. Congenital cataract (affecting 400,000 newborns yearly worldwide), associated with 54 mutations in beta gamma-crystallins, occurs in two major phenotypes nuclear cataract, which blocks the central visual axis, hampering the development of the growing eye and demanding earliest intervention, and the milder peripheral progressive cataract where surgery can wait. In order to understand this phenotypic dichotomy at the molecular level, we have studied the structural and aggregation features of representative mutations. Methods: Wild type and several representative mutant proteins were cloned, expressed and purified and their secondary and tertiary structural details, as well as structural stability, were compared in solution, using spectroscopy. Their tendencies to aggregate in vitro and in cellulo were also compared. In addition, we analyzed their structural differences by molecular modeling in silico. Results: Based on their properties, mutants are seen to fall into two classes. Mutants A36P, L45PL54P, R140X, and G165fs display lowered solubility and structural stability, expose several buried residues to the surface, aggregate in vitro and in cellulo, and disturb/distort the Greek key motif. And they are associated with nuclear cataract. In contrast, mutants P24T and R77S, associated with peripheral cataract, behave quite similar to the wild type molecule, and do not affect the Greek key topology. Conclusion: When a mutation distorts even one of the four Greek key motifs, the protein readily self-aggregates and precipitates, consistent with the phenotype of nuclear cataract, while mutations not affecting the motif display `native state aggregation', leading to peripheral cataract, thus offering a protein structural rationale for the cataract phenotypic dichotomy ``distort motif, lose central vision''.

From Selective-ID to Full-ID IBS without Random Oracles

Since its induction, the selective-identity (sID) model for identity-based cryptosystems and its relationship with various other notions of security has been extensively studied. As a result, it is a general consensus that the sID model is much weaker than the full-identity (ID) model. In this paper, we study the sID model for the particular case of identity-based signatures (IBS). The main focus is on the problem of constructing an ID-secure IBS given an sID-secure IBS without using random oracles-the so-called standard model-and with reasonable security degradation. We accomplish this by devising a generic construction which uses as black-box: i) a chameleon hash function and ii) a weakly-secure public-key signature. We argue that the resulting IBS is ID-secure but with a tightness gap of O(q(s)), where q(s) is the upper bound on the number of signature queries that the adversary is allowed to make. To the best of our knowledge, this is the first attempt at such a generic construction.