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Folding of Alzheimer's core PHF subunit revealed by monoclonal antibody 423

Rostislav Skrabana1, Peter Kontsek, Anna Mederlyova

  • 1Axon Neuroscience, Rennweg 95b, 1030 Vienna, Austria.

FEBS Letters
|June 16, 2004
PubMed

Insights

Monoclonal antibody MN423 recognizes specific Alzheimer's disease (AD) core paired helical filaments (PHF) structures. This study identifies three tau segments critical for this recognition, aiding in structure-based drug design for AD.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Structural Biology

Background:

  • Conformation-dependent monoclonal antibodies (mAbs) are crucial for studying tau protein folding in paired helical filaments (PHFs).
  • Monoclonal antibody MN423 specifically recognizes Alzheimer's disease (AD) core PHF subunits terminating at Glu391.

Purpose of the Study:

  • To elucidate the structural components recognized by mAb 423 within the core PHF subunit.
  • To identify the specific tau protein segments involved in the conformational structure targeted by mAb 423.

Main Methods:

  • Utilized recombinant analogs of core PHF subunits (tau residues 297-391).
  • Generated deletion mutants of the core subunit to pinpoint structural components.
  • Employed mAb 423 binding assays to map epitope regions.

Main Results:

  • The C-terminal pentapeptide (387)DHGAE(391) is one component recognized by mAb 423.
  • Two additional spatially proximate segments, (306)VQIVYK(311) and (321)KCGSL(325), were identified as crucial for mAb 423 binding.
  • The spatial proximity of these three segments imposes intramolecular folding constraints on the core PHF subunit.

Conclusions:

  • The structure recognized by mAb 423 involves three distinct tau segments: (306)VQIVYK(311), (321)KCGSL(325), and (387)DHGAE(391).
  • This detailed structural understanding of PHF subunits can inform structure-based drug design strategies targeting AD.

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