Trypanosoma cruzi macrophage infectivity potentiator has a rotamase core and a highly exposed alpha-helix.
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.
Pereira
Pedro José Barbosa
PJ
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.
Vega
M Cristina
MC
González-Rey
Elena
E
Fernández-Carazo
Rafael
R
Macedo-Ribeiro
Sandra
S
Gomis-Rüth
F Xavier
FX
González
Antonio
A
Coll
Miquel
M
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
D001426:Bacterial Proteins; D008565:Membrane Proteins; D015800:Protozoan Proteins; D022021:Tacrolimus Binding Proteins; D020104:Immunophilins; C512922:Mip protein, Legionella pneumophila; D019696:Peptidylprolyl Isomerase