The Structure of Chagasin in Complex with a Cysteine Protease Clarifies the Binding Mode and Evolution of an Inhibitor Family

Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
Structure (Impact Factor: 5.62). 06/2007; 15(5):535-43. DOI: 10.1016/j.str.2007.03.012
Source: PubMed


Protein inhibitors of proteolytic enzymes regulate proteolysis and prevent the pathological effects of excess endogenous or exogenous proteases. Cysteine proteases are a large family of enzymes found throughout the plant and animal kingdoms. Disturbance of the equilibrium between cysteine proteases and natural inhibitors is a key event in the pathogenesis of cancer, rheumatoid arthritis, osteoporosis, and emphysema. A family (I42) of cysteine protease inhibitors ( was discovered in protozoan parasites and recently found widely distributed in prokaryotes and eukaryotes. We report the 2.2 A crystal structure of the signature member of the I42 family, chagasin, in complex with a cysteine protease. Chagasin has a unique variant of the immunoglobulin fold with homology to human CD8alpha. Interactions of chagasin with a target protease are reminiscent of the cystatin family inhibitors. Protein inhibitors of cysteine proteases may have evolved more than once on nonhomologous scaffolds.

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    • "We aligned the sequences of falstatin and PbICP with those of other ICPs. Falstatin and it plasmodial homologues have long stretches of amino acids that are absent in chagasin and homologues from Leishmania mexicana and Cryptosporidium parvum [11], [12], [32] (Fig. 1). Overall, the sequence similarity between falstatin and chagasin is ∼20%, and that between falstatin and PbICP is ∼38%. "
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    • "However, most peptidase inhibitors are secreted and intracellular peptidase inhibitors are rare. The only examples are cystatins A and B from family I25, which inhibit cysteine peptidases 9; calpastatin, which inhibits the intracellular peptidase calpain 10; chagasin from the zooflagellate Leishmania (family I42), which also inhibits cysteine peptidases 11; three intracellular coagulation inhibitors from the horseshoe crab Tachypleus that are serpins from family I4 12; and pinA from family I24, which is an inhibitor of the ATP-dependent serine endopeptidase Lon, but is of unknown structure 13. Despite the inhibitors being intracellular, the known target peptidases are all extracellular, with the exceptions of calpain and endopeptidase Lon. "
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    • "The inhibitors from these families have completely different folds but still use different loops to occlude the active-site residues. In contrast to two loops in clitocypins, proteins such as cystatins, thyropins, and chagasin provide three loops, which fi ll the active-site cleft (Stubbs et al. , 1990 ; Gunč ar et al., 1999 ; Wang et al. , 2007 ; Redzynia et al. , 2008 ). "
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