title: Crystal structure of the Leishmania major MIX protein: a scaffold protein that mediates protein-protein interactions.
abstract: Infection by Leishmania and Trypanosoma causes severe disease and can be fatal. The reduced effectiveness of current treatments is largely due to drug resistance, hence the urgent need to develop new drugs, preferably against novel targets. We have recently identified a mitochondrial membrane-anchored protein, designated MIX, which occurs exclusively in these parasites and is essential for virulence. We have determined the crystal structure of Leishmania major MIX to a resolution of 2.4 Å. MIX forms an all α-helical fold comprising seven α-helices that fold into a single domain. The distribution of helices is similar to a number of scaffold proteins, namely HEAT repeats, 14-3-3, and tetratricopeptide repeat proteins, suggesting that MIX mediates protein-protein interactions. Accordingly, using copurification and mass spectroscopy we were able to identify several proteins that may interact with MIX in vivo. Being parasite specific, MIX is a promising new drug target and, thus, the structure and potential interacting partners provide a basis for structure-guided drug discovery.
authors.affiliation: Biota Structural Biology Laboratory, St. Vincent's Institute of Medical Research, Victoria 3065, Australia.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gorman
authors.forename: Alex D
authors.initials: AD
authors.lastname: Uboldi
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Walsh
authors.forename: Kher Shing
authors.initials: KS
authors.lastname: Tan
authors.forename: Guido
authors.initials: G
authors.lastname: Hansen
authors.forename: Trevor
authors.initials: T
authors.lastname: Huyton
authors.forename: Hong
authors.initials: H
authors.lastname: Ji
authors.forename: Joan
authors.initials: J
authors.lastname: Curtis
authors.forename: Lukasz
authors.initials: L
authors.lastname: Kedzierski
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Papenfuss
authors.forename: Con
authors.initials: C
authors.lastname: Dogovski
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Perugini
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Simpson
authors.forename: Emanuela
authors.initials: E
authors.lastname: Handman
authors.forename: Michael W
authors.initials: MW
authors.lastname: Parker
mesh_terms: D048948:14-3-3 Proteins / Q000737:chemistry* / Q000378:metabolism; D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D006801:Humans; D018320:Leishmania major / Q000737:chemistry* / Q000378:metabolism; D016773:Leishmaniasis, Cutaneous / Q000469:parasitology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D025941:Protein Interaction Mapping; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000737:chemistry* / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: D048948:14-3-3 Proteins; D015800:Protozoan Proteins