Folding of the Tau Protein on Microtubules.

Microtubules are regulated by microtubule-associated proteins. However, little is known about the structure of microtubule-associated proteins in complex with microtubules. Herein we show that the microtubule-associated protein Tau, which is intrinsically disordered in solution, locally folds into a stable structure upon binding to microtubules. While Tau is highly flexible in solution and adopts a β-sheet structure in amyloid fibrils, in complex with microtubules the conserved hexapeptides at the beginning of the Tau repeats two and three convert into a hairpin conformation. Thus, binding to microtubules stabilizes a unique conformation in Tau.

[1]  J. Ávila,et al.  Localization of the tubulin binding site for tau protein. , 1985, European journal of biochemistry.

[2]  E. Mandelkow,et al.  Domains of tau protein and interactions with microtubules. , 1994, Biochemistry.

[3]  E. Mandelkow,et al.  β-Sheet core of tau paired helical filaments revealed by solid-state NMR. , 2012, Journal of the American Chemical Society.

[4]  E. Mandelkow,et al.  Characterization of Alzheimer's-like paired helical filaments from the core domain of tau protein using solid-state NMR spectroscopy. , 2008, Journal of the American Chemical Society.

[5]  M. Goedert,et al.  Repeat motifs of tau bind to the insides of microtubules in the absence of taxol , 2003, The EMBO journal.

[6]  S. Feinstein,et al.  Evidence for two distinct binding sites for tau on microtubules. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[7]  M. Kirschner,et al.  Beyond self-assembly: From microtubules to morphogenesis , 1986, Cell.

[8]  Ronald C. Petersen,et al.  Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17 , 1998, Nature.

[9]  H. Kawasaki,et al.  A common amino acid sequence in 190-kDa microtubule-associated protein and tau for the promotion of microtubule assembly. , 1989, The Journal of biological chemistry.

[10]  I. Landrieu,et al.  Accepting its Random Coil Nature Allows a Partial NMR Assignment of the Neuronal Tau Protein , 2004, Chembiochem : a European journal of chemical biology.

[11]  P. Tittmann,et al.  Surface-decoration of microtubules by human tau. , 2004, Journal of molecular biology.

[12]  Ewa A. Mirecka,et al.  Alternative Conformations of the Tau Repeat Domain in Complex with an Engineered Binding Protein* , 2014, The Journal of Biological Chemistry.

[13]  C. Schmidt,et al.  Tau protein binding forms a 1 nm thick layer along protofilaments without affecting the radial elasticity of microtubules. , 2007, Journal of structural biology.

[14]  M. Kirschner,et al.  A protein factor essential for microtubule assembly. , 1975, Proceedings of the National Academy of Sciences of the United States of America.

[15]  D. Craik,et al.  Role of phosphorylation in the conformation of tau peptides implicated in Alzheimer's disease. , 2000, Biochemistry.

[16]  W. Goux.  The conformations of filamentous and soluble tau associated with Alzheimer paired helical filaments. , 2002, Biochemistry.

[17]  Jocelyn T. Compton,et al.  Tau mutants bind tubulin heterodimers with enhanced affinity , 2014, Proceedings of the National Academy of Sciences.

[18]  M. Goedert,et al.  The repeat region of microtubule-associated protein tau forms part of the core of the paired helical filament of Alzheimer's disease. , 1989, Annals of medicine.

[19]  L. Buée,et al.  Proline‐Directed Random‐Coil Chemical Shift Values as a Tool for the NMR Assignment of the Tau Phosphorylation Sites , 2004, Chembiochem : a European journal of chemical biology.

[20]  A. Klug,et al.  Structural characterization of the core of the paired helical filament of Alzheimer disease. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[21]  M. Kirschner,et al.  Tau protein binds to microtubules through a flexible array of distributed weak sites , 1991, The Journal of cell biology.

[22]  M. Kirschner,et al.  Tau protein function in living cells , 1986, The Journal of cell biology.

[23]  S. Halpain,et al.  MAP2 and tau bind longitudinally along the outer ridges of microtubule protofilaments , 2002, The Journal of cell biology.

[24]  D. Eliezer,et al.  Binding of the three-repeat domain of tau to phospholipid membranes induces an aggregated-like state of the protein. , 2012, Biochimica et biophysica acta.

[25]  N. Hirokawa,et al.  Projection domains of MAP2 and tau determine spacings between microtubules in dendrites and axons , 1992, Nature.

[26]  E. Mandelkow,et al.  Hsp90-Tau Complex Reveals Molecular Basis for Specificity in Chaperone Action , 2014, Cell.

[27]  R. A. Crowther,et al.  Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease , 1989, Neuron.

[28]  S. Yokoyama,et al.  Interaction mechanism between microtubule-associated proteins and microtubules. A proton nuclear magnetic resonance analysis on the binding of synthetic peptide to tubulin. , 1990, Biochemistry.

[29]  I. Landrieu,et al.  NMR investigation of the interaction between the neuronal protein tau and the microtubules. , 2007, Biochemistry.

[30]  I. Landrieu,et al.  Mechanism of Tau-promoted microtubule assembly as probed by NMR spectroscopy. , 2014, Journal of the American Chemical Society.

[31]  D. Eliezer,et al.  Residual structure in the repeat domain of tau: echoes of microtubule binding and paired helical filament formation. , 2005, Biochemistry.

[32]  Christian Griesinger,et al.  Structural Polymorphism of 441-Residue Tau at Single Residue Resolution , 2009, PLoS biology.

[33]  E. Mandelkow,et al.  Stepwise proteolysis liberates tau fragments that nucleate the Alzheimer-like aggregation of full-length tau in a neuronal cell model , 2007, Proceedings of the National Academy of Sciences.

[34]  D. Eliezer,et al.  Assigning Backbone NMR Resonances for Full Length Tau Isoforms: Efficient Compromise between Manual Assignments and Reduced Dimensionality , 2012, PloS one.

[35]  M. Kirschner,et al.  Physical and chemical properties of purified tau factor and the role of tau in microtubule assembly. , 1977, Journal of molecular biology.

[36]  D. Cleveland,et al.  Going new places using an old MAP: tau, microtubules and human neurodegenerative disease. , 2001, Current opinion in cell biology.

[37]  C. Post.  Exchange-transferred NOE spectroscopy and bound ligand structure determination. , 2003, Current opinion in structural biology.

[38]  Nobutaka Hirokawa,et al.  Molecular motors and mechanisms of directional transport in neurons , 2005, Nature Reviews Neuroscience.

[39]  S. Feinstein,et al.  Kinetic stabilization of microtubule dynamics at steady state by tau and microtubule-binding domains of tau. , 1995, Biochemistry.