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

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• 作者：Skrabana ; Rostislav ; Kontsek ; Peter ; Mederlyova ; Anna ; Iqbal ; Khalid ; Novak ; Michal
• 关键词：Alzheimer's disease ; Tau protein ; Truncation ; Paired helical filament ; AD ; Alzheimer's disease ; ECL ; enhanced chemiluminescence ; ELISA ; enzyme linked immunosorbent assay ; mAb ; monoclonal antibody ; NMR ; nuclear magnetic resonance ; PBS ; phosphate buffered s
• 刊名：FEBS Letters
• 出版年：2004
• 出版时间：June 18, 2004
• 年：2004
• 卷：568
• 期：1-3
• 页码：178-182
• 全文大小：202 K

文摘

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 τ297–391, we found that the C-terminal pentapeptide ³⁸⁷DHGAE³⁹¹ 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 (³⁰⁶VQIVYK³¹¹ and ³²¹KCGSL³²⁵) contributing to formation of the structure identified by mAb 423. Thus, the spatial proximity of three subunit segments ³⁰⁶VQIVYK³¹¹, ³²¹KCGSL³²⁵ and ³⁸⁷DHGAE³⁹¹ 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.