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J. Biol. Chem., Vol. 275, Issue 20, 15572-15577, May 19, 2000

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J Biol Chem, Vol. 275, Issue 20, 15572-15577, May 19, 2000

Saxiphilin, a Saxitoxin-binding Protein with Two Thyroglobulin Type 1 Domains, Is an Inhibitor of Papain-like Cysteine Proteinases^*

Brigita Lenari^§, Gomathi Krishnan^¶, Renata Borukhovich^¶, Brian Ruck^¶, Vito Turk, and Edward Moczydlowski^¶

From the Departments of  Biochemistry and Molecular Biology, J. Stefan Institute, Jamova 39, 1000 Ljubljana, Slovenia and the Departments of ^¶ Pharmacology and  Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520-8066

The type 1 domain of thyroglobulin is a protein module (Thyr-1) that occurs in a variety of secreted and membrane proteins. Several examples of Thyr-1 modules have been previously identified as inhibitors of the papain family of cysteine proteinases. Saxiphilin is a neurotoxin-binding protein from bullfrog and a homolog of transferrin with a pair of such Thyr-1 modules located in the N-lobe. Saxiphilin is now characterized as a potent inhibitor of three cysteine proteinases as follows: papain, human cathepsin B, and cathepsin L. The stoichiometry of enzyme inhibition reveals that both Thyr-1 domains of saxiphilin inhibit papain (apparent K_i = 1.72 nM), but only one of these domains inhibits cathepsin B (K_i = 1.67 nM) and cathepsin L (K_i = 0.02 nM). Physical association of saxiphilin and papain blocked from turnover at the active-site cysteine residue can be detected by cross-linking with glutaraldehyde. The rate of association of saxiphilin and cathepsin B is strongly pH-dependent with an optimum at pH 5.2, reflecting control by at least two H⁺-titratable groups. These results further demonstrate that various Thyr-1 domains are selective inhibitors of cysteine proteinases with utility in the study of protein interactions and degradation.

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