Isoelectric Focusing of Crystallins in Microsections of Calf and Adult Bovine Lens

Babizhayev, Mark A.; Bours, J.; Utikal, Klaus J.

doi:10.1159/000267931

Cited by 8 publications

(4 citation statements)

References 14 publications

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“…Given these results, it is interesting to note that the amount of α-crystallin found associated with the membrane dramatically increases with both increasing age and cataract formation ( , ). It has also been found that the amount of soluble α-crystallin decreases under the same conditions ( − ). Although it is unclear what relationship may exist between membrane binding, progressive insolubilization of α-crystallin, and cataract formation, the present results suggest that membrane association could be an important component of the opacification in age-related cataracts as well as in congenital cataracts associated with the R116C mutation.…”

Section: Discussionmentioning

confidence: 91%

“…Other studies that characterized the distribution of α-crystallin in normal, aged, and cataractous lenses showed that the amount of soluble α-crystallin found in the cytoplasm of fiber cells falls steadily with increasing age and/or presence of cataract. Furthermore, these changes appear to be mirrored by an increase in the abundance of α-crystallin in the water-insoluble fraction from lens homogenates ( − ). The prevailing explanation for these observations is that the amount of soluble α-crystallin available to bind partially denatured lens proteins becomes depleted with age, and any further protein denaturation results in the formation of light scattering aggregates.…”

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confidence: 99%

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Structural and Functional Changes in the αA-Crystallin R116C Mutant in Hereditary Cataracts

2000

Biochemistry

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alpha-Crystallin, the major protein component of vertebrate lenses, forms a large complex comprised of two homologous subunits, alphaA- and alphaB-crystallin. It has the ability to suppress stress-induced protein aggregation in vitro, bind saturably to lens plasma membranes, and aid in light refraction through short-range ordering. Recently, a missense mutation in alphaA-crystallin that changes arginine 116 to a cysteine residue (R116C) was genetically linked to one form of autosomal dominant congenital cataracts. This point mutation is reported to cause structural alterations at many levels as well as a 4-fold reduction in chaperone-like activity. To extend these findings, we examined the quaternary stability of the alphaA R116C mutant protein and its effect on chaperone-like activity, subunit exchange, and membrane association. Homocomplexes of mutant subunits become highly polydisperse following incubation at 37 degrees C, reflecting the likely in vivo distribution of the complexes. Chaperone-like activity of the alphaA R116C mutant is approximately 4-fold lower than wild type, whether measured before or after conversion to a polydisperse population with incubation. alphaA R116C complexes also have a 4-fold reduced ability to exchange subunits with wild-type complexes. Finally, membrane binding capacity measurements of mutant subunits showed a 10-fold increase over wild type. Our results, in conjunction with previous reports, suggest that the changes in complex polydispersity, the reduction of subunit exchange, and increased membrane binding capacity are all potential factors in the pathogenesis of alphaA R116C associated congenital cataracts.

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Section: Discussionmentioning

confidence: 91%

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confidence: 99%

Structural and Functional Changes in the αA-Crystallin R116C Mutant in Hereditary Cataracts

2000

Biochemistry

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“…Among these causes, aging is the most common cause of cataract formation in which the association of α-crystallin to the eye lens's fiber cell plasma membrane increases progressively [59][60][61][62][63][64][65]. With age and at the onset of cataract formation, water-soluble α-crystallin slowly depletes to the insoluble aggregates [61,63,64,[66][67][68][69]; however, the nature of such insoluble aggregates is not well characterized [63,[67][68][69][70][71][72][73][74]. In the human lens nucleus, the most pronounced conversion of soluble to insoluble α-crystallin and the corresponding conversion of soluble to insoluble high molecular weight (HMW) protein occurs after the age of 40 [63,67,68].…”

Section: Introductionmentioning

confidence: 99%

Association of Alpha-Crystallin with Fiber Cell Plasma Membrane of the Eye Lens Accompanied by Light Scattering and Cataract Formation

Timsina

Mainali

2021

Membranes

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α-crystallin is a major protein found in the mammalian eye lens that works as a molecular chaperone by preventing the aggregation of proteins and providing tolerance to stress in the eye lens. These functions of α-crystallin are significant for maintaining lens transparency. However, with age and cataract formation, the concentration of α-crystallin in the eye lens cytoplasm decreases with a corresponding increase in the membrane-bound α-crystallin, accompanied by increased light scattering. The purpose of this review is to summarize previous and recent findings of the role of the: 1) lens membrane components, i.e., the major phospholipids (PLs) and sphingolipids, cholesterol (Chol), cholesterol bilayer domains (CBDs), and the integral membrane proteins aquaporin-0 (AQP0; formally MIP26) and connexins, and 2) α-crystallin mutations and post-translational modifications (PTMs) in the association of α-crystallin to the eye lens’s fiber cell plasma membrane, providing thorough insights into a molecular basis of such an association. Furthermore, this review highlights the current knowledge and need for further studies to understand the fundamental molecular processes involved in the association of α-crystallin to the lens membrane, potentially leading to new avenues for preventing cataract formation and progression.

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“…It is thought that these complexes arise directly from R-crystallin's ability to bind damaged proteins and prevent their aggregation into inclusion bodies. In addition, R-crystallin is known to fractionate increasingly with the water-insoluble fraction of the lens with age, although the nature of that insoluble fraction has not been studied in detail (27)(28)(29)(30)(31). In separate reports, the amount of crystallin protein, particularly R-crystallin, found on the membranes during cataract formation is dramatically increased over the basal levels (10).…”

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confidence: 99%

α-Crystallin Chaperone-like Activity and Membrane Binding in Age-Related Cataracts

Cobb

Petrash

2001

Biochemistry

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α-Crystallin, the major protein component of the vertebrate lens, is thought to play a critical role in the maintenance of transparency through its ability to inhibit stress-induced protein aggregation. However, during aging and cataract formation the amount of membrane-bound α-crystallin increases significantly while high molecular weight complexes (HMWCs) comprised of α-crystallin and other lens crystallins accumulate. These and other recent data suggest a possible link between cataract formation, the formation of high molecular weight α-crystallin aggregates, and the progressive increase in membrane association of α-crystallin. To better understand these processes, we characterized the chaperone-like activity (CLA) and subunit exchange of membrane bound αcrystallin. In addition, we measured the membrane binding properties of in vitro constituted HMWCs to understand the mechanism by which increased α-crystallin is bound to the membrane of old and cataractous lens cells in vivo. Membrane-associated α-crystallin complexes have measurably reduced CLA compared to complexes in solution; however, membrane binding does not alter the time required for α-crystallin complexes to reach subunit exchange equilibrium. In addition, HMWCs prepared in vitro have a profoundly increased membrane binding capacity as compared to native α-crystallin. These results are consistent with a model in which increased membrane binding of α-crystallin is an integral step in the pathogenesis of many forms of cataracts.

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Isoelectric Focusing of Crystallins in Microsections of Calf and Adult Bovine Lens

Cited by 8 publications

References 14 publications

Structural and Functional Changes in the αA-Crystallin R116C Mutant in Hereditary Cataracts

Structural and Functional Changes in the αA-Crystallin R116C Mutant in Hereditary Cataracts

Association of Alpha-Crystallin with Fiber Cell Plasma Membrane of the Eye Lens Accompanied by Light Scattering and Cataract Formation

α-Crystallin Chaperone-like Activity and Membrane Binding in Age-Related Cataracts

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