The structure of bradyzoite-specific enolase from Toxoplasma gondii reveals insights into its dual cytoplasmic and nuclear functions
- Northwestern Univ., Chicago, IL (United States). Center for Structural Genomics of Infectious Diseases
- Univ. Lille Nord de France (France). Inst. Pasteur de Lille, Center for Infection and Immunity of Lille
- Univ. Lille Nord de France (France). Inst. Pasteur de Lille, Center for Infection and Immunity of Lille
- Northwestern Univ., Chicago, IL (United States). Center for Structural Genomics of Infectious Diseases; BrainMicro LLC, New Haven, CT (United States)
In addition to catalyzing a central step in glycolysis, enolase assumes a remarkably diverse set of secondary functions in different organisms, including transcription regulation as documented for the oncogene c-Myc promoter-binding protein 1. The apicomplexan parasite Toxoplasma gondii differentially expresses two nuclear-localized, plant-like enolases: enolase 1 (TgENO1) in the latent bradyzoite cyst stage and enolase 2 (TgENO2) in the rapidly replicative tachyzoite stage. A 2.75 Å resolution crystal structure of bradyzoite enolase 1, the second structure to be reported of a bradyzoite-specific protein inToxoplasma, captures an open conformational state and reveals that distinctive plant-like insertions are located on surface loops. The enolase 1 structure reveals that a unique residue, Glu164, in catalytic loop 2 may account for the lower activity of this cyst-stage isozyme. Recombinant TgENO1 specifically binds to a TTTTCT DNA motif present in the cyst matrix antigen 1 (TgMAG1) gene promoter as demonstrated by gel retardation. Furthermore, direct physical interactions of both nuclear TgENO1 and TgENO2 with the TgMAG1 gene promoter are demonstrated n vivo using chromatin immunoprecipitation (ChIP) assays. Structural and biochemical studies reveal that T. gondii enolase functions are multifaceted, including the coordination of gene regulation in parasitic stage development. Lastly, enolase 1 provides a potential lead in the design of drugs against Toxoplasma brain cysts.
- Research Organization:
- Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Organization:
- USDOE; National Institutes of Health (NIH); France National Agency for Research
- Grant/Contract Number:
- AC02-06CH11357; HHSN272200700058C; HHSN272201200026C; 085P1000817; 3RO1DAO13141- 08S1
- OSTI ID:
- 1172406
- Journal Information:
- Acta Crystallographica. Section D: Biological Crystallography (Online), Vol. 71, Issue 3; ISSN 1399-0047
- Publisher:
- International Union of CrystallographyCopyright Statement
- Country of Publication:
- United States
- Language:
- ENGLISH
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