Structural characterization of monoclonal antibodies targeting C-terminal Ser404 region of phosphorylated tau protein

MAbs
Jessica E ChukwuXiang-Peng Kong

Abstract

Targeting tau with immunotherapies is currently the most common approach taken in clinical trials of patients with Alzheimer's disease. The most prominent pathological feature of tau is its hyperphosphorylation, which may cause the protein to aggregate into toxic assemblies that collectively lead to neurodegeneration. Of the phospho-epitopes, the region around Ser396/Ser404 has received particular attention for therapeutic targeting because of its prominence and stability in diseased tissue. Herein, we present the antigen-binding fragment (Fab)/epitope complex structures of three different monoclonal antibodies (mAbs) that target the pSer404 tau epitope region. Most notably, these structures reveal an antigen conformation similar to a previously described pathogenic tau epitope, pSer422, which was shown to have a β-strand structure that may be linked to the seeding core in tau oligomers. In addition, we have previously reported on the similarly ordered conformation observed in a pSer396 epitope, which is in tandem with pSer404. Our data are the first Fab structures of mAbs bound to this epitope region of the tau protein and support the existence of proteopathic tau conformations stabilized by specific phosphorylation events tha...Continue Reading

References

Mar 15, 1991·Proceedings of the National Academy of Sciences of the United States of America·R A Crowther
Nov 1, 1991·The Journal of Cell Biology·K A Butner, M W Kirschner
Jul 1, 1988·Proceedings of the National Academy of Sciences of the United States of America·C M WischikR A Crowther
Jul 1, 1986·Proceedings of the National Academy of Sciences of the United States of America·I Grundke-IqbalL I Binder
Jan 1, 1996·Acta Neurologica Scandinavica. Supplementum·H Braak, E Braak
Oct 24, 2002·Acta Crystallographica. Section D, Biological Crystallography·Paul D AdamsThomas C Terwilliger
Jul 11, 2003·Proceedings of the National Academy of Sciences of the United States of America·John BerrimanR Anthony Crowther
Jul 9, 2004·Proceedings of the National Academy of Sciences of the United States of America·Martin Margittai, Ralf Langen
Jul 21, 2004·Journal of Computational Chemistry·Eric F PettersenThomas E Ferrin
Aug 24, 2007·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Ayodeji A AsuniEinar M Sigurdsson
Dec 20, 2007·Journal of Neurochemistry·Claudie HooperSimon Lovestone
Jul 30, 2008·The European Journal of Neuroscience·Natasha DetersJürgen Götz
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Wolfgang Kabsch
Dec 15, 2010·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Allal BoutajangoutEinar M Sigurdsson
Oct 26, 2011·Frontiers in Psychiatry·Pavan K KrishnamurthyEinar M Sigurdsson
Apr 11, 2012·Journal of Neuropathology and Experimental Neurology·Peter T NelsonThomas G Beach
Jul 22, 2014·Journal of Neurochemistry·Arne IttnerLars M Ittner
Dec 2, 2014·Pharmacology & Therapeutics·Eleonore BeurelRichard S Jope
Dec 17, 2014·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Senthilkumar KrishnaswamyEinar M Sigurdsson
Mar 31, 2015·Annals of Clinical and Translational Neurology·Tomohiro UmedaTakami Tomiyama
Apr 8, 2015·Trends in Molecular Medicine·Jan Torleif Pedersen, Einar M Sigurdsson
Aug 1, 2015·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Daniel KanmertDominic M Walsh
Oct 19, 2016·Alzheimer's & Dementia : the Journal of the Alzheimer's Association·Dov B ShamirEinar M Sigurdsson
Aug 27, 2016·Journal of Molecular Biology·Mark B SwindellsAndrew C R Martin
Dec 9, 2016·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Wencheng LiuSteven M Paul
Apr 15, 2017·The American Journal of Pathology·Chloe K NobuharaShuko Takeda
Jul 6, 2017·Nature·Anthony W P FitzpatrickSjors H W Scheres

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Methods Mentioned

BETA
ELISA
enzyme-linked immunosorbent assays
x-ray crystallography
size-exclusion chromatography

Software Mentioned

PDBePISA
abYsis
XDS
PyMOL
GenScript
Chimera

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