Protein Inhibitors of Crystal Growth

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Abstract
Nephrocalcin is a urinary glycopeptide that may be a physiological inhibitor of nephrolithiasis. Monomeric nephrocalcin purified from ethylenediaminetetracetic acid-treated urine is 14,000 daltons. Compositional analyses indicate that nephrocalcin is 10 per cent carbohydrate by weight and that 25 per cent of the amino acid residues are acidic (glutamic acid, aspartic acid and gamma-carboxyglutamic acid). Nephrocalcin binds reversibly to calcium oxalate crystals with a dissociation constant of about 0.5 microM. The high collapse pressure of nephrocalcin, 41.5 dynes per cm., measured for a monolayer at the air-water interface, suggests a highly organized structure in which hydrophilic and hydrophobic regions occupy separate regions on the surface of the inhibitor. Nephrocalcin contains the unusual amino acid, gamma-carboxyglutamic acid. Nephrocalcin isolated from urine of stone formers and from kidney stones does not contain gamma-carboxyglutamic acid and it has altered surface properties compared to normal nephrocalcin. The presence of the gamma-carboxyglutamic acid modification and the ability to form stable films with high collapse pressures may be important factors enabling nephrocalcin to prevent stone formation in vivo. The blood of cold water fishes contains antifreeze glycopeptides and/or peptides to prevent it from freezing. The structure of one such antifreeze peptide and its interactions with the crystal lattice of hexagonal ice are discussed as a model for how nephrocalcin might interact with calcium oxalate crystals and arrest their growth in urine.