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P1‐220: A STRUCTURE‐BASED MODEL FOR THE ELECTROSTATIC INTERACTION OF THE N‐TERMINUS OF PROTEIN TAU WITH THE FIBRIL CORE OF ALZHEIMER'S DISEASE FILAMENTS
Author(s) -
Boyer David,
Eisenberg David S.
Publication year - 2019
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2019.06.775
Subject(s) - fibril , protein filament , crystallography , chemistry , core (optical fiber) , tau protein , biophysics , core model , materials science , alzheimer's disease , biochemistry , biology , disease , medicine , pathology , mathematical analysis , mathematics , composite material
Background:Although portions of tau protein within the microtubule binding region have been shown to form the ordered core of tau fibrils, the structural details of how other regions of tau participate in fibril formation are so far unknown. In an attempt to understand how the N-terminus of tau may interact with the fibril core, we crystallized and determined the structure of the N-terminal segment 5RQEFEV10 of tau. Several lines of evidence have shown the importance of this segment for fibril formation. Methods:We crystallized RQEFEV using the hanging drop vapor diffusion method, and we collected X-ray diffraction data at the Advanced Photon Source. We phased the RQEFEV diffraction data by molecular replacement, and we modeled the interaction of the RQEFEV crystal structure with the core of Alzheimer’s disease fibrils in COOT. Results: The RQEFEV crystal structure reveals an out-ofregister Class 5 steric zipper with a wet and a dry interface. Our structure-based model of the interaction of RQEFEV with the AD Paired Helical Filament (PHF) fibril core demonstrates that the wet interface glutamates from RQEFEV can form electrostatic interactions with lysines 317 and 321 in the fibril core. In addition, we find that a hereditary mutation Arg5Leu found in a patient with PSP results in a stronger interaction of the N-terminus with the AD PHF fibril core in our model. Unlike the PHF, modeling of the RQEFEV crystal structure onto the AD Straight Filament (SF) structure did not result in a plausible model. We instead think that Lys317 and Lys321 must interact with some other counteranion in the AD SF structure.Conclusions: Ourmodel of the binding of the wet interface of the RQEFEV structure with the 313VDLSKVTSKC322 region of the Alzheimer’s Disease tau fibrils structures helps illuminate the possible mechanism of interaction between these two segments, distant in sequence. Our model helps to support previous literature, such as epitope mapping of the Alz50 and MC-1 antibodies, that shows that the N-terminus of tau interacts with a region of Repeat 3 in tau fibrils. In addition, our model points toward the possible conservation of this interaction across multiple polymorphs of tau.