title: 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.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Stephanie X
authors.initials: SX
authors.lastname: Wang
authors.forename: Kailash C
authors.initials: KC
authors.lastname: Pandey
authors.forename: Julio
authors.initials: J
authors.lastname: Scharfstein
authors.forename: James
authors.initials: J
authors.lastname: Whisstock
authors.forename: Rick K
authors.initials: RK
authors.lastname: Huang
authors.forename: Jordan
authors.initials: J
authors.lastname: Jacobelli
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Fletterick
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.forename: Magnus
authors.initials: M
authors.lastname: Abrahamson
authors.forename: Linda S
authors.initials: LS
authors.lastname: Brinen
authors.forename: Andrea
authors.initials: A
authors.lastname: Rossi
authors.forename: Andrej
authors.initials: A
authors.lastname: Sali
authors.forename: James H
authors.initials: JH
authors.lastname: McKerrow
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003546:Cysteine Endopeptidases / Q000737:chemistry* / Q000502:physiology; D019143:Evolution, Molecular; D008969:Molecular Sequence Data; D005810:Multigene Family; D011480:Protease Inhibitors; D011485:Protein Binding / Q000502:physiology; D015800:Protozoan Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D014349:Trypanosoma cruzi / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D011480:Protease Inhibitors; D015800:Protozoan Proteins; C435145:chagasin, Trypanosoma; D003546:Cysteine Endopeptidases