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(Received for publication, August 21, 1996)
From the Departments of ¶ Ophthalmology and Visual
Sciences, One of the major protein components of the ocular
lens,
Volume 271, Number 50,
Issue of December 13, 1996
pp. 31973-31980
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
A-Crystallin
,
Biochemistry and Molecular Biophysics, and
Genetics, Washington University School of Medicine,
St. Louis, Missouri 63110
-crystallin, is composed of A and B chain subunits that
have structural homology to the family of mammalian small heat shock
proteins. Like other small heat shock proteins, -crystallin subunits
associate to form large oligomeric aggregates that express
chaperone-like activity, as defined by the ability to suppress
nonspecific aggregation of proteins destabilized by treatment with a
variety of denaturants including heat, UV irradiation, and chemical
modification. It has been proposed that age-related loss of sequences
at the C terminus of the A chain subunit may be a factor in the
pathogenesis of cataract due to diminished capacity of the truncated
crystallin to protect against nonspecific aggregation of lens proteins.
To evaluate the functional consequences of -crystallin modification, two mutant forms of A subunits were prepared by site-directed mutagenesis. Like wild type (WT), aggregates of ~540 kDa were formed
from a tryptophan-free A mutant (W9F). When added in stoichiometric amounts, both WT and W9F subunits completely suppressed the
heat-induced aggregation of aldose reductase. In contrast, subunits
encoded by a truncation mutant in which the C-terminal 17 residues were deleted (R157STOP), despite having spectroscopic properties similar to
WT, formed much larger aggregates with a marked reduction in chaperone-like activity. Similar results were observed when the chaperone-like activity was assessed through inhibition of
-crystallin aggregation induced by singlet oxygen. These results
demonstrate that the structurally conservative substitution of Phe for
Trp-9 has a negligible effect on the functional interaction of
A subunits, and that deletion of C-terminal sequences from the A
subunit results in substantial loss of chaperone-like activity, despite overall preservation of secondary structure.
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