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Multi-domain O-GlcNAcase structures reveal allosteric regulatory mechanisms.

Sara Basse Hansen1, Sergio G Bartual1, Huijie Yuan1,2

  • 1Section for Neurobiology and DANDRITE, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.

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The O-GlcNAc hydrolase (OGA) pseudo-histone acetyltransferase (pHAT) domain forms dimers and influences enzyme activity. This pHAT domain

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • Nucleocytoplasmic protein O-GlcNAcylation is regulated by O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase (OGA).
  • The O-GlcNAc hydrolase (OGA) enzyme possesses a pseudo-histone acetyltransferase (pHAT) domain, whose structure and function are largely unknown.
  • Understanding OGA regulation is crucial for elucidating O-GlcNAc homeostasis.

Purpose of the Study:

  • To determine the structure and function of the O-GlcNAc hydrolase (OGA) pseudo-histone acetyltransferase (pHAT) domain.
  • To investigate the role of the pHAT domain in the multi-domain structure and activity of OGA.
  • To reveal the allosteric mechanisms governing O-GlcNAc homeostasis.

Main Methods:

  • X-ray crystallography to determine the structure of the Trichoplax adhaerens pHAT domain.
  • Cryo-electron microscopy (cryo-EM) to resolve the structure of multi-domain T. adhaerens and human OGAs.
  • Biophysical analyses to characterize OGA domain interactions and conformational flexibility.

Main Results:

  • The eukaryotic OGA pHAT domain forms catalytically incompetent, symmetric homodimers with a putative peptide-binding site.
  • In solution, OGA exists as flexible multi-domain dimers, with linker interactions restricting pHAT domain movement.
  • pHAT domain movements in human OGA induce conformational changes in a flexible arm, remodeling the active site environment.

Conclusions:

  • The OGA pHAT domain plays a crucial role in regulating O-GlcNAc hydrolase activity through allosteric mechanisms.
  • Structural insights into the pHAT domain and its interactions provide a basis for understanding O-GlcNAc homeostasis.
  • These findings uncover novel regulatory pathways impacting O-GlcNAc modification dynamics.