The structure of chagasin in complex with a cysteine protease clarifies the binding mode and evolution of an inhibitor family.

Abstract

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 (http://merops.sanger.ac.uk) 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.

• Authors: Stephanie X Wang, Kailash C Pandey, Julio Scharfstein, James Whisstock, Rick K Huang, Jordan Jacobelli, Robert J Fletterick, Philip J Rosenthal, Magnus Abrahamson, Linda S Brinen, Andrea Rossi, Andrej Sali, James H McKerrow
• Journal: Structure (London, England : 1993) (Structure) Vol. 15 Issue 5 Pg. 535-43 (May 2007) ISSN: 0969-2126 [Print] United States
• PMID: 17502099 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Protease Inhibitors
• Protozoan Proteins
• chagasin, Trypanosoma
• Cysteine Endopeptidases

Topics

• Amino Acid Sequence
• Animals
• Cysteine Endopeptidases (chemistry, physiology)
• Evolution, Molecular
• Molecular Sequence Data
• Multigene Family
• Protease Inhibitors
• Protein Binding (physiology)
• Protozoan Proteins (chemistry, genetics, metabolism)
• Trypanosoma cruzi (chemistry, genetics, metabolism)