Randolpf V. Lewis

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Henryk Mach

Universidad Complutense de Madrid

Phillip A. TrautmanS

C. Russell Middaughnli

John A. Thomson

Johns Hopkins Hospital

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Universidad Complutense de Madrid

National Centre for Nuclear Research

United States Military Academy

Merck & Co., Inc., Rahway, NJ, USA (United States)

University of Notre Dame

Ohio University

Kocaeli Üniversitesi

Uppsala University

Institut de Recherche Vaccinale

University of Wyoming

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Inhibition of cw-Crystallin Aggregation by y-Crystallin"

Henryk Mach Phillip A. TrautmanS John A. Thomson Randolpf V. Lewis C. Russell Middaughnli

The transparency of the mammalian lens is primarily maintained by short range order among the major pro- teins of the lens fiber cells, the crystallins. Although these proteins are highly conserved at the amino acid sequence level, it has proven difficult to establish that they possess other than structural functions. We find that when non-lens proteins are added to concentrated solutions of a-crystallin, aggregation is induced, pre- sumably through excluded volume effects. In contrast, the monomeric y-crystallins and the low molecular weight form of &crystallin (pL) cause a decrease in the size of cr-crystallin. When the naturally aggregated form of cY-crystallin is examined, y- and &-crystallin, as well as a reducing agent, also cause partial dissocia- tion as detected by dynamic light scattering and size exclusion chromatography, while no effect is seen with non-crystallin proteins. Furthermore, the chemical cross-linking of cY-crystallin is inhibited by y- and &- crystallin but not by other proteins. The ability of y- crystallin to inhibit the association of a-crystallin is primarily localized to the r-11 form which contains a high degree of exposed thiols. Only small amounts of y- and fiL-crystallin, however, can be cross-linked to cw-crystallin in mixtures of the three proteins even at very high protein concentrations. These results suggest that one possible role for the lower molecular weight crystallins may be to minimize through a reductive effect the intrinsic tendency of cr-crystallin to aggre- gate, an association reaction implicated in the loss of lens transparency. The transparency of the vertebrate ocular lens appears to be derived largely through short range order among the con- centrated proteins of the lens fiber cells, the crystallins (1,2). The crystallins are a group of soluble globular proteins which are expressed at extremely high concentrations in the lens and whose primary function appears to be to establish an essential refractive index gradient (3). It is now generally accepted that any significant disruption of the crystallin’s short range order, regardless of the mechanism or etiologic pathway, will result in increased light scattering by the lens tissue and, consequently, lens opacification or cataract for- * This work was partially supported by the National Eye Institute, National Institutes of Health Grant EY06727, and National Institute of Health Research Career Development Award AI00663 (to C. R. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked

Crystallin

Thiol

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