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Title: The structure of bradyzoite-specific enolase from Toxoplasma gondii reveals insights into its dual cytoplasmic and nuclear functions

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 potentialmore » lead in the design of drugs against Toxoplasma brain cysts.« less
Authors:
 [1] ;  [2] ;  [1] ;  [1] ;  [1] ;  [3] ;  [4]
  1. Northwestern Univ., Chicago, IL (United States). Center for Structural Genomics of Infectious Diseases
  2. Univ. Lille Nord de France (France). Inst. Pasteur de Lille, Center for Infection and Immunity of Lille
  3. Univ. Lille Nord de France (France). Inst. Pasteur de Lille, Center for Infection and Immunity of Lille
  4. Northwestern Univ., Chicago, IL (United States). Center for Structural Genomics of Infectious Diseases; BrainMicro LLC, New Haven, CT (United States)
Publication Date:
OSTI Identifier:
1172406
Grant/Contract Number:
AC02-06CH11357; HHSN272200700058C; HHSN272201200026C; 085P1000817; 3RO1DAO13141- 08S1
Type:
Accepted Manuscript
Journal Name:
Acta Crystallographica. Section D: Biological Crystallography (Online)
Additional Journal Information:
Journal Name: Acta Crystallographica. Section D: Biological Crystallography (Online); Journal Volume: 71; Journal Issue: 3; Journal ID: ISSN 1399-0047
Publisher:
International Union of Crystallography
Research Org:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org:
USDOE; National Institutes of Health (NIH); France National Agency for Research
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; moonlighting protein; brain parasite; central nervous system; chronic infection; differentiation