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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAEY000255-24
Application #
8556805
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
24
Fiscal Year
2012
Total Cost
$572,245
Indirect Cost
Name
U.S. National Eye Institute
Department
Type
DUNS #
City
State
Country
Zip Code
Sagar, Vatsala; Chaturvedi, Sumit K; Schuck, Peter et al. (2017) Crystal Structure of Chicken ?S-Crystallin Reveals Lattice Contacts with Implications for Function in the Lens and the Evolution of the ??-Crystallins. Structure 25:1068-1078.e2
Chen, Yingwei; Sagar, Vatsala; Len, Hoay-Shuen et al. (2016) ?-Crystallins of the chicken lens: remnants of an ancient vertebrate gene family in birds. FEBS J 283:1516-30
Zhao, Huaying; Chen, Yingwei; Rezabkova, Lenka et al. (2014) Solution properties of ?-crystallins: hydration of fish and mammal ?-crystallins. Protein Sci 23:88-99
Slingsby, Christine; Wistow, Graeme J (2014) Functions of crystallins in and out of lens: roles in elongated and post-mitotic cells. Prog Biophys Mol Biol 115:52-67
Chen, Yingwei; Zhao, Huaying; Schuck, Peter et al. (2014) Solution properties of ?-crystallins: compact structure and low frictional ratio are conserved properties of diverse ?-crystallins. Protein Sci 23:76-87
Wistow, Graeme J; Slingsby, Christine (2014) Editorial for special issue: crystallins of the eye. Prog Biophys Mol Biol 115:1-2
Slingsby, Christine; Wistow, Graeme J; Clark, Alice R (2013) Evolution of crystallins for a role in the vertebrate eye lens. Protein Sci 22:367-80
Mahler, Bryon; Chen, Yingwei; Ford, Jason et al. (2013) Structure and dynamics of the fish eye lens protein, ?M7-crystallin. Biochemistry 52:3579-87
Fan, Jianguo; Dong, Lijin; Mishra, Sanghamitra et al. (2012) A role for ?S-crystallin in the organization of actin and fiber cell maturation in the mouse lens. FEBS J 279:2892-904
Wistow, Graeme (2012) The human crystallin gene families. Hum Genomics 6:26

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