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Intra- and intermolecular beta-pleated sheet formation in glutamine-repeat inserted myoglobin as a model for

M Tanaka1, I Morishima, T Akagi

  • 1Laboratory for CAG repeat diseases, RIKEN Brain Science Institute, Saitama 351-0198, Japan.

The Journal of Biological Chemistry
|October 5, 2001
PubMed

Insights

Expanded polyglutamine structures form antiparallel beta-pleated sheets, driving aggregate formation in CAG repeat diseases. This molecular model reveals how polyglutamine aggregation contributes to disease pathology.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • CAG repeat diseases are linked to aberrant polyglutamine structures.
  • Understanding polyglutamine aggregation is crucial for disease mechanism elucidation.

Purpose of the Study:

  • To investigate the structural properties of expanded polyglutamine.
  • To characterize a molecular model for polyglutamine diseases.

Main Methods:

  • Sperm whale myoglobin mutants with varying glutamine repeat lengths were engineered.
  • Circular dichroism, IR spectroscopy, fluorescence, and NMR spectroscopy were employed.
  • Monoclonal antibody 1C2 was used for recognition of expanded polyglutamine.

Main Results:

  • Expanded polyglutamine in Gln(28), Gln(35), and Gln(50) Mb forms antiparallel beta-pleated sheet structures.
  • Gln(50) Mb aggregates consist of intermolecular antiparallel beta-pleated sheets.
  • Partial protein surface unfolding was observed in Gln(35) and Gln(50) Mb.

Conclusions:

  • The fluctuating beta-pleated sheet of expanded polyglutamine on the protein surface promotes aggregate formation.
  • This study provides the first characterization of a molecular model for polyglutamine diseases.

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