Eye lens zeta-crystallin relationships to the family of "long-chain" alcohol/polyol dehydrogenases. Protein trimming and conservation of stable parts.

zeta-Crystallin of guinea pig lens is distantly related to the family of zinc-containing alcohol/polyol dehydrogenases. The amino acid residues binding the catalytic zinc atom in the alcohol dehydrogenase are exchanged in zeta-crystallin, explaining lack of known enzyme activity, and those residues binding the noncatalytic zinc in the dehydrogenase are located in a segment absent from the crystallin. Mammalian alcohol dehydrogenase, polyol dehydrogenase, and zeta-crystallin therefore constitute a series of proteins exhibiting successive changes in subunit metal content, from two to one and probably zero zinc atoms, respectively. In common with tetrameric dehydrogenases, the crystallin lacks a loop structure present in the dimeric dehydrogenase. Significantly, the crystallin is tetrameric, and a correlation between extra subunit interactions and lack of the loop segment is indicated. The lacking segment in crystallin is extended, encompassing a second loop in the dehydrogenase. The greatest conservation corresponds to the coenzyme-binding domain of the dehydrogenases, the central parts of which are remarkably similar to those in the crystallin. Glycine is by far the most conserved residue and corresponds to positions at bends in the conformation of the alcohol dehydrogenase. The conservation of the stable parts of the fold, the absence of the loop structure, the lack of the metal atoms, and the presence of only a small proportion of oxidation-sensitive cysteine residues in crystallin (5 versus 15 in the beta 1 dehydrogenase subunit) suggest an increased stability of the lens protein and a derivation from the alcohol dehydrogenase family. This is compatible with the recruitment of stable enzyme structures for lens crystallin functions, with trimming of protein structures through these dehydrogenases or a yet unknown enzyme, and with multiple changes in the dehydrogenase family.