% IMPORTANT: The following is UTF-8 encoded.  This means that in the presence
% of non-ASCII characters, it will not work with BibTeX 0.99 or older.
% Instead, you should use an up-to-date BibTeX implementation like “bibtex8” or
% “biber”.

@PHDTHESIS{Chinnathambi:270141,
      author       = {Chinnathambi, Subash},
      title        = {{I}nfluence of {P}hosphorylation on the {P}athological
                      {C}onformation of {H}uman {M}icrotubule {A}ssociated
                      {P}rotein {T}au},
      school       = {Universität Hamburg},
      type         = {Dissertation},
      reportid     = {DZNE-2024-00741},
      pages        = {159 pages},
      year         = {2011},
      note         = {Dissertation, Universität Hamburg, 2011},
      abstract     = {Tau is one of the microtubule associated proteins which can
                      bind and stabilize microtubules. It is classified as a
                      natively unfolded protein. It has a very low content of
                      secondary structural elements. Tau aggregates into insoluble
                      fibers called paired helical filaments in Alzheimer’s
                      disease. The residual folding and intramolecular
                      interactions within tau are largely unknown, and the factors
                      contributing to the formation and stability of PHFs and
                      different morphologies of PHFs are not well understood.The
                      results of the present studies are aimed at better
                      understanding of the effect of phosphorylation on the
                      aggregation propensity and tau microtubule interaction.The
                      effect of phosphorylation sites in the KXGS motifs within
                      the repeats and in the SP/TP motifs of the flanking regions
                      were studied. We also studied tau fibrilpolymorphism by
                      Electron Microscopy and Atomic Force Microscopy. We further
                      studied tau in solution by increasing temperature using
                      different biophysical methods (CD spectroscopy, static and
                      dynamic light scattering and small angle x-ray scattering).
                      These observations could form a basis for elucidating the
                      molecular and physiological role of phosphorylation at the
                      repeat domains and in the flanking regions. The results are
                      summarized as follows(i) The pseudo-phosphorylation of KXGE
                      motifs within the repeat domains of tau has a strong
                      negative effect on both the tau-microtubule interaction and
                      the aggregation into paired helical filaments. KXGE mutants
                      on the basis of three repeat domain and four repeat domain
                      constructs show a low tendency to aggregate and form
                      amorphous aggregates instead of PHFs. Pseudo-phosphorylation
                      in the SP/TP motifs in the N- and C-terminal domains of the
                      flanking regions has only a moderate effect, both on the
                      tau-microtubule interaction and on the aggregation into
                      paired helical filaments. Overall, the results show that the
                      physiological tau-microtubule interaction and the
                      pathological tau-tau interaction similarly can be influenced
                      by phosphorylation.(ii) The combined pseudo-phosphorylation
                      of AT8* and PHF1 sites leads to compaction of the paperclip
                      conformation, such that the N-terminus approaches the repeat
                      domain. When the Cterminus tail is cleaved from tau, the
                      compaction becomes even stronger by combining
                      pseudophosphorylated AT8*, AT100, and PHF1 epitopes. This is
                      accompanied by a strong increase in the reaction with
                      conformation-dependent antibodies MC1 and Alz-50, suggesting
                      the generation of a pathological conformation characteristic
                      of tau in AD. Furthermore, the compact paperclip
                      conformation enhances the aggregation propensity to paired
                      helical filaments but has little effect on microtubule
                      interactions. Discussion 89(iii) High resolution atomic
                      force and electron microscopy were employed to study
                      fibrilsassembled from different human tau isoforms and
                      domains. All fibrils reveal structuralpolymorphism: the
                      “thin twisted” and “thin smooth” fibrils resemble
                      flat ribbons(cross-section ~10 x 15 nm) with diverse twist
                      periodicities. “Thick fibrils” show periodicities of
                      ~65-70 nm and thicknesses of ~9-18 nm as routinely reported
                      for“paired helical filaments” but structurally resemble
                      heavily twisted ribbons.Therefore, thin and thick fibrils
                      assembled from different human tau isoforms challenge
                      current structural models of paired helical filaments. The
                      full-length tau and repeat domain constructs assemble into
                      fibrils of similar thickness, the “fuzzy coat” of tau
                      protein termini surrounding the fibril axis is nearly
                      invisible for atomicforce microscopy and electron
                      microscopy, presumably because of its high flexibility.(iv)
                      The unfolded nature of tau protein allows it to adopt either
                      more extended or compact conformations. It is intriguing to
                      speculate that the compaction and memory effect observed
                      after rapid heating/cooling may be related to the compaction
                      observed upon hyperphosphorylation, characteristic of
                      incipient neuronal degeneration in AD. The “memory
                      effect” is observed with full-length tau, but not with the
                      repeat domain alone, suggesting that the interplay between
                      domains in the whole protein might be responsible for the
                      effect. One possible explanation could be the interplay
                      between the acidic N-terminal domain (which varies among the
                      tau isoforms due to alternative splicing) and the basic
                      repeat domain (which also differs between the isoforms).},
      cin          = {AG Mandelkow 1},
      cid          = {I:(DE-2719)1013014},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)11},
      urn          = {urn:nbn:de:gbv:18-56123},
      url          = {https://pub.dzne.de/record/270141},
}