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X‐ray structure of the PHF core C‐terminus: Insight into the folding of the intrinsically disordered protein tau in Alzheimer's disease
Author(s) -
Sevcik Jozef,
Skrabana Rostislav,
Dvorsky Radovan,
Csokova Natalia,
Iqbal Khalid,
Novak Michal
Publication year - 2007
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.2007.11.067
Subject(s) - folding (dsp implementation) , protein folding , core (optical fiber) , disease , chemistry , c terminus , biophysics , crystallography , physics , medicine , biology , biochemistry , pathology , amino acid , electrical engineering , engineering , optics
The major constituent of Alzheimer's disease paired helical filaments (PHF) core is intrinsically disordered protein (IDP) tau. In spite of a considerable effort, insoluble character of PHF together with inherent physical properties of IDP tau have precluded so far reconstruction of PHF 3D structure by X‐ray crystallography or NMR spectroscopy. Here we present first crystallographic study of PHF core C‐terminus. Using monoclonal antibody MN423 specific to the tertiary structure of the PHF core, the in vivo PHF structure was imprinted into recombinant core PHF tau. Crystallization of the complex led to determination of the structure of the core PHF tau protein fragment 386 TDHGAE 391 at 1.65 Å resolution. Structural analysis suggests important role of the core PHF C‐terminus for PHF assembly. It is reasonable to expect that this approach will help to reveal the structural principles underlying the tau protein assembly into PHF and possibly will facilitate rationale drug design for inhibition of Alzheimer neurofibrillary changes.