Molecular Structure and Function of Crystallins

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gamma-crystallins are associated with cataract in both human and animal models. gS-crystallin is the major bg-crystallin in the adult human lens and has also been found to be induced in retinal pigment epithelium in models of macular degeneration. The gene for gS has been ablated in mouse, leading to disruption of normal fiber cell maturation. This is associated with abnormalities in key components of the architecture of the fiber cells, suggesting a functional role for crystallins in maintaining cell structure both in lens and elsewhere in the eye. In particular, loss of gS leads to defects in organization of actin while gS can stabilize F-actin in vitro. Examination of older knockout mice is also providing evidence for defects in retina that may provide a model for aging. Collaborative studies using NMR structure analysis are shedding light on the processes of unfolding and amyloid formation involving crystallins and the chaperone role of a-crystallin. This has wider significance for understanding how normally folded proteins can unfold and adopt other structures that can have serious consequences for cellular function. The same technique has also been used to determine the first structure of a gM-crystallin from fish, representing an extreme member of the family in terms of composition and behavior. To explore the functional characteristics of g-crystallins, proteins from fish and birds representing the extremes of the family in composition and behavior have been expressed. Using recombinant g-crystallins in several biophysical studies, we have shown that they have highly unusual solution properties that fit them for high protein concentration environments and shed light on how they unfold under stress.