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Folding of Alzheimer's core PHF subunit revealed by monoclonal antibody 423
Author(s) -
Skrabana Rostislav,
Kontsek Peter,
Mederlyova Anna,
Iqbal Khalid,
Novak Michal
Publication year - 2004
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2004.04.098
Subject(s) - monoclonal antibody , protein subunit , chemistry , pentapeptide repeat , folding (dsp implementation) , core (optical fiber) , recombinant dna , microbiology and biotechnology , antibody , biophysics , biochemistry , biology , peptide , immunology , materials science , electrical engineering , composite material , gene , engineering
At present, the conformation‐dependent monoclonal antibodies (mAb) provide the only information on folding of tau in the core PHF. Monoclonal antibody MN423 recognizes all and only those Alzheimer's disease (AD) core paired helical filaments (PHFs) subunits, which terminate at Glu391. Using recombinant analogs of the core PHF subunit corresponding to tau residues τ 297–391, we found that the C‐terminal pentapeptide 387 DHGAE 391 represented only one component of the structure recognized by mAb 423. Therefore, deletion mutants of the core subunit were generated to identify assembled parts of this conformational structure. We localized two spatially close components in the region 306–325 ( 306 VQIVYK 311 and 321 KCGSL 325 ) contributing to formation of the structure identified by mAb 423. Thus, the spatial proximity of three subunit segments 306 VQIVYK 311 , 321 KCGSL 325 and 387 DHGAE 391 represents constraints for intramolecular folding of the core PHF subunit. Since PHF represents a compelling drug target in AD, structural knowledge presented could contribute to structure‐based drug design.