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Joseph Horwitz – One of the best experts on this subject based on the ideXlab platform.
Alpha Crystallin the quest for a homogeneous quaternary structureExperimental Eye Research, 2009Co-Authors: Joseph HorwitzAbstract:
Alpha A and Alpha B Crystallins are key members of the small heat-shock protein family. In addition to being a major structural protein of the lens, they are constitutively found in many other cells, where their function is not completely understood. Alpha B Crystallin is also known to be over-expressed in many neurological diseases. To date, all efforts to crystallize Alpha A or Alpha B have failed. Thus, high-resolution data on the tertiary and quaternary structures of Alpha Crystallin is not available. The main reason for this failure seems to be the polydisperse nature of Alpha Crystallin. This review deals mainly with the polydisperse properties of Alpha Crystallin and the influence of post-translational modification, chemical modifications, truncations and mutation on its quaternary structure.
the function of Alpha Crystallin in visionSeminars in Cell & Developmental Biology, 2000Co-Authors: Joseph HorwitzAbstract:
Abstract The Alpha–Crystallins account for approximately one-third of the total soluble protein in the lens, contributing to its refractive power. In addition, Alpha–Crystallin also has a chaperone-like function and thus can bind unfolding lens proteins. Alpha B-Crystallin is also found outside the lens, having an extensive tissue distribution. It is over-expressed in response to stresses of all kinds, where it is thought to serve a general protective function. Recently, it has been shown in humans that naturally occurring point mutations in the Alpha–Crystallins result in a deficit in chaperone-like function, and cause cataracts as well as a desmin-related myopathy. This review summarizes much of the past and current knowledge concerning the structure and functions of Alpha–Crystallin.
Interaction of .Alpha.-Crystallin with Spin-Labeled PeptidesBiochemistry, 1995Co-Authors: Zohreh Toossi Farahbakhsh, Qingling Huang, Linlin Ding, Christian Altenbach, Heinz-juergen Steinhoff, Joseph Horwitz, Wayne L. HubbellAbstract:
Alpha–Crystallin is a major protein of the vertebrate lens once thought to be highly specialized for conferring transparency. However, recent work has revealed a wide tissue distribution and a sequence homology to small heat shock proteins, suggesting a more general role for the protein. Like other molecular chaperons, Alpha–Crystallin is known to bind to unfolded proteins and suppress nonspecific aggregation in vitro. In the present work, spin-labeled derivatives of the insulin B chain and melittin were used to investigate the state of these proteins bound to Alpha–Crystallin. Insulin was selected since unfolding can be triggered by reduction of the interchain disulfide bonds, a treatment that does not affect Alpha–Crystallin. Upon reduction of insulin, the separated B chains aggregate. In the presence of Alpha–Crystallin, the B chains bind to Alpha–Crystallin and aggregation is suppressed. Melittin, a 26 amino acid peptide from bee venom, was selected for study since it is a random coil under physiological conditions, and its interaction with Alpha–Crystallin can be directly studied. EPR analysis of the spin-labeled peptides shows that the nitroxide side chains are immobilized in a polar environment on Alpha–Crystallin and that they are separated by 25 A or more in the complex, indicating that the bound proteins are not clustered. The bound B chains of insulin are not in a fully extended conformation, and melittin does not appear to bind to a hydrophobic surface in Alpha–Crystallin as an amphipathic helix, as it does to membranes and some other proteins.(ABSTRACT TRUNCATED AT 250 WORDS)
Roger J.w. Truscott – One of the best experts on this subject based on the ideXlab platform.
Presbyopia and heat: changes associated with aging of the human lens suggest a functional role for the small heat shock protein, Alpha–Crystallin, in maintaining lens flexibility.Aging cell, 2007Co-Authors: Karl R Heys, Michael G Friedrich, Roger J.w. TruscottAbstract:
Presbyopia, the inability to focus up close, affects everyone by age 50 and is the most common eye condition. It is thought to result from changes to the lens over time making it less flexible. We present evidence that presbyopia may be the result of age-related changes to the proteins of the lens fibre cells. Specifically, we show that there is a progressive decrease in the concentration of the chaperone, Alpha–Crystallin, in human lens nuclei with age, as it becomes incorporated into high molecular weight aggregates and insoluble protein. This is accompanied by a large increase in lens stiffness. Stiffness increases even more dramatically after middle age following the disappearance of free soluble Alpha–Crystallin from the centre of the lens. These alterations in Alpha–Crystallin and aggregated protein in human lenses can be reproduced simply by exposing intact pig lenses to elevated temperatures, for example, 50 degrees C. In this model system, the same protein changes are also associated with a progressive increase in lens stiffness. These data suggest a functional role for Alpha–Crystallin in the human lens acting as a small heat shock protein and helping to maintain lens flexibility. Presbyopia may be the result of a loss of Alpha–Crystallin coupled with progressive heat-induced denaturation of structural proteins in the lens during the first five decades of life.
W W De Jong – One of the best experts on this subject based on the ideXlab platform.
Mutations and modifications support a ‘pitted-flexiball’ model for Alpha–Crystallin.International journal of biological macromolecules, 1998Co-Authors: R H Smulders, M A Van Boekel, W W De JongAbstract:
Alpha–Crystallin is renown for resisting crystallization and electron microscopic image analysis. The spatial conformation thus remaining elusive, the authors explored the structure and chaperone functioning by analyzing the effects of site-directed mutagenesis, the properties of naturally occurring aberrant forms of Alpha–Crystallin and the influence of chemical modifications. The authors observed that the globular multimeric structure, as well as the chaperoning capacity are remarkably tolerant towards changes and modifications in the primary structure. The essential features of the quaternary structure–globular shape, flexibility, highly polar exterior and accessible hydrophobic surface pockets–support a ‘pitted-flexiball’ model, which combines tetrameric subunit building blocks in an open micelle-like arrangement.
The influence of some post-translational modifications on the chaperone-like activity of Alpha–Crystallin.Ophthalmic research, 1996Co-Authors: M A Van Boekel, J J Harding, S E Hoogakker, W W De JongAbstract:
We investigated the influence of phosphorylation, glycation, carbamylation and oxidative modification on the capacity of Alpha–Crystallin to protect beta-Crystallins against heat denaturation. Simple modification of lysine residues by early glycation or carbamylation had no effect. However, late (cross-linking) glycation products and oxidative modifications decreased the chaperone-like activity of Alpha–Crystallin. Homopolymers of Alpha A-Crystallin had a higher protecting capacity compared with those of Alpha B-Crystallin. The in vivo phosphorylated forms of especially Alpha A- but also Alpha B-Crystallin revealed a somewhat better protecting ability than the respective non-phosphorylated forms.
Evolution of the Alpha–Crystallin/small heat-shock protein family.Molecular Biology and Evolution, 1993Co-Authors: W W De Jong, J A M Leunissen, C. E. M. VoorterAbstract:
Abstract The common characteristic of the Alpha–Crystallin/small heat-shock protein family is the presence of a conserved homologous sequence of 90-100 residues. Apart from the vertebrate lens proteins–Alpha A- and Alpha B-Crystallin–and the ubiquitous group of 15-30-kDa heat-shock proteins, this family also includes two mycobacterial surface antigens and a major egg antigen of Schistosoma mansoni. Multiple small heat-shock proteins are especially present in higher plants, where they can be distinguished in at least two classes of cytoplasmic proteins and a chloroplast-located class. The Alpha–Crystallins have recently been found in many tissues outside the lens, and Alpha B-Crystallin, in particular, behaves in many respects like a small heat-shock protein. The homologous sequences constitute the C-terminal halves of the proteins and probably represent a structural domain with a more variable C-terminal extension. These domains must be responsible for the common structural and functional properties of this protein family. Analysis of the phylogenetic tree and comparison of the biological properties of the various proteins in this family suggest the following scenario for its evolution: The primordial role of the small heat-shock protein family must have been to cope with the destabilizing effects of stressful conditions on cellular integrity. The Alpha–Crystallin-like domain appears to be very stable, which makes it suitable both as a surface antigen in parasitic organisms and as a long-living lens protein in vertebrates. It has recently been demonstrated that, like the other heat-shock proteins, the Alpha–Crystallins and small heat-shock proteins function as molecular chaperones, preventing undesired protein-protein interactions and assisting in refolding of denatured proteins. Many of the small heat-shock proteins are differentially expressed during normal development, and there is good evidence that they are involved in cytomorphological reorganizations and in degenerative diseases. In conjunction with the stabilizing, thermoprotective role of Alpha–Crystallins and small heat-shock proteins, they may also be involved in signal transduction. The reversible phosphorylation of these proteins appears to be important in this respect.