title: Trypanosoma cruzi macrophage infectivity potentiator has a rotamase core and a highly exposed alpha-helix.
abstract: The macrophage infectivity potentiator protein from Trypanosoma cruzi (TcMIP) is a major virulence factor secreted by the etiological agent of Chagas' disease. It is functionally involved in host cell invasion. We have determined the three-dimensional crystal structure of TcMIP at 1.7 A resolution. The monomeric protein displays a peptidyl-prolyl cis-trans isomerase (PPIase) core, encompassing the characteristic rotamase hydrophobic active site, thus explaining the strong inhibition of TcMIP by the immunosuppressant FK506 and related drugs. In TcMIP, the twisted beta-sheet of the core is extended by an extra beta-strand, preceded by a long, exposed N-terminal alpha-helix, which might be a target recognition element. An invasion assay shows that the MIP protein from Legionella pneumophila (LpMIP), which has an equivalent N-terminal alpha-helix, can substitute for TcMIP. An additional exposed alpha-helix, this one unique to TcMIP, is located in the C-terminus of the protein. The high-resolution structure reported here opens the possibility for the design of new inhibitory drugs that might be useful for the clinical treatment of American trypanosomiasis.
authors.affiliation: Institut de Biología Molecular-CSIC, Jordi Girona 18-26, E-08034 Barcelona and 1Instituto de Parasitología y Biomedicina-CSIC, Ventanilla 11, E-18001 Granada, Spain.
authors.forename: Pedro José Barbosa
authors.initials: PJ
authors.lastname: Pereira
authors.forename: M Cristina
authors.initials: MC
authors.lastname: Vega
authors.forename: Elena
authors.initials: E
authors.lastname: González-Rey
authors.forename: Rafael
authors.initials: R
authors.lastname: Fernández-Carazo
authors.forename: Sandra
authors.initials: S
authors.lastname: Macedo-Ribeiro
authors.forename: F Xavier
authors.initials: FX
authors.lastname: Gomis-Rüth
authors.forename: Antonio
authors.initials: A
authors.lastname: González
authors.forename: Miquel
authors.initials: M
authors.lastname: Coll
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001426:Bacterial Proteins; D001665:Binding Sites; D006801:Humans; D020104:Immunophilins / Q000737:chemistry*; D008264:Macrophages; D008565:Membrane Proteins / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019696:Peptidylprolyl Isomerase / Q000737:chemistry*; D017433:Protein Structure, Secondary; D015800:Protozoan Proteins / Q000737:chemistry* / Q000502:physiology; D017385:Sequence Homology; D017386:Sequence Homology, Amino Acid; D022021:Tacrolimus Binding Proteins / Q000737:chemistry; D014349:Trypanosoma cruzi / Q000737:chemistry* / Q000201:enzymology / Q000502:physiology
chemical_list: D001426:Bacterial Proteins; D008565:Membrane Proteins; D015800:Protozoan Proteins; D022021:Tacrolimus Binding Proteins; D020104:Immunophilins; C512922:Mip protein, Legionella pneumophila; D019696:Peptidylprolyl Isomerase