Malarial EBA-175 region VI crystallographic structure reveals a KIX-like binding interface.
The malaria parasite proliferates in the bloodstream of its vertebrate host by invading and replicating within erythrocytes. To achieve successful invasion, a number of discrete and essential events need to take place at the parasite-host cell interface. Erythrocyte-binding antigen 175 (EBA-175) is a member of a family of Plasmodium falciparum erythrocyte-binding proteins involved in the formation of a tight junction, a necessary step in invasion. Here we present the crystal structure of EBA-175 region VI (rVI), a cysteine-rich domain that is highly conserved within the protein family and is essential for EBA-175 trafficking. The structure was solved by selenomethionine single-wavelength anomalous dispersion at 1.8 A resolution. It reveals a homodimer, containing in each subunit a compact five-alpha-helix core that is stabilized by four conserved disulfide bridges. rVI adopts a novel fold that is likely conserved across the protein family, indicating a conserved function. It shows no similarity to the Duffy-binding-like domains of EBA-175 involved in erythrocyte binding, indicating a distinct role. Remarkably, rVI possesses structural features related to the KIX-binding domain of the coactivator CREB-binding protein, supporting the binding and trafficking roles that have been ascribed to it and providing a rational basis for further experimental investigation of its function.
Division of Parasitology, National Institute for Medical Research, Mill Hill, London NW7 1AA, UK. cmartin@nimr.mrc.ac.uk
Chrislaine
C
Withers-Martinez
Lesley F
LF
Haire
Fiona
F
Hackett
Philip A
PA
Walker
Steven A
SA
Howell
Stephen J
SJ
Smerdon
Guy G
GG
Dodson
Michael J
MJ
Blackman
D000595:Amino Acid Sequence; D000818:Animals; D000953:Antigens, Protozoan; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003545:Cysteine / Q000737:chemistry; D019281:Dimerization; D004220:Disulfides / Q000737:chemistry; D004375:Duffy Blood-Group System / Q000737:chemistry / Q000378:metabolism*; D004912:Erythrocytes / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D008288:Malaria / Q000097:blood*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D008970:Molecular Weight; D010963:Plasmodium falciparum / Q000737:chemistry* / Q000378:metabolism* / Q000472:pathogenicity; D011485:Protein Binding; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000097:blood*; D017386:Sequence Homology, Amino Acid; D014867:Water / Q000737:chemistry
D000953:Antigens, Protozoan; D004220:Disulfides; D004375:Duffy Blood-Group System; D015800:Protozoan Proteins; D014867:Water; D003545:Cysteine