abg-Crystallins are the major protein components in the vertebrate eye lens
- a as a molecular chaperone and b and g as structural proteins. Surprisin
gly, the latter two share some structural characteristics with a number of
microbial stress proteins. The common denominator is not only the Greek key
topology of their polypeptide chains but also their high intrinsic stabili
ty, which, in certain microbial crystallin homologs, is further enhanced by
high-affinity Ca2+-binding. Recent studies of natural and mutant vertebrat
e bg-crystallins as well as spherulin 3a from Physarum polycephalum and Pro
tein S from Myxococcus xanthus allowed the correlation of structure and sta
bility of crystallins to be elucidated in some detail. From the thermodynam
ic point of view, stability increments come from (1) local interactions inv
olved in the close packing of the cooperative units, (2) the all-b secondar
y structure of the Greek-key motif, (3) intramolecular interactions between
domains, (4) intermolecular domain interactions, including 3D domain swapp
ing and (v) excluded volume effects due to "molecular crowding" at the high
cellular protein concentrations. Apart from these contributions to the Gib
bs free energy of stability, significant kinetic stabilization originates f
rom the high activation energy barrier determining the rate of unfolding fr
om the native to the unfolded state. From the functional point of view, the
high stability is responsible for the long-term transparency of the eye le
ns, on the one hand, and the stress resistance of the microorganisms in the
ir dormant state on the other. Local structural perturbations due to chemic
al modification, wrong protein interactions, or other irreversible processe
s may lead to protein aggregation. A leading cataract hypothesis is that on
ly after a-crystallin, a member of the small heat-shock protein family, is
titrated out does pathological opacity occur. Understanding the structural
basis of protein stability in the healthy eye lens is the route to solve th
e enormous medical and economical problem of cataract.