Identification of an Aggregation-Prone Structure of Tau
Open accessAbstract
The aggregation and deposition of normally soluble proteins is the hallmark of several devastating neurodegenerative disorders. For proteins such as tau in Alzheimer's disease and α-synuclein in Parkinson's disease, aggregation involves a transition from an intrinsically disordered monomer to a highly structured fiber. While understanding the role of these proteins in neurodegeneration requires elucidation of the structural basis of self-association, the conformational heterogeneity of disordered proteins makes their structural characterization inherently challenging. Here we use single molecule Förster resonance energy transfer to measure the conformational ensemble of tau in the absence and presence of heparin to identify critical conformational changes relevant to the initiation of aggregation. We find that different domains of tau display distinct conformational properties that are strongly correlated with their degree of disorder and that may relate to their roles in aggregation. Moreover, we observe that heparin binding induces a distinct two-state structural transition in tau characterized by a loss of long-range contacts and a concomitant compaction of the microtubule binding domain. Our results describe a conformational intermediate of tau that precedes the formation of aggregates and could serve as a target for tau-focused therapeutics.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Tau bound heparin with an affinity of 4.6 ± 0.6 nM.
“Tau bound heparin with an affinity of 4.6 ± 0.6 nM, consistent with previous reports26.”
From Tau Internalization is Regulated by 6-O Sulfation on Heparan Sulfate Proteoglycans (HSPGs) (2018) · cites this paper as [26]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Protein Misfolding, Functional Amyloid, and Human Disease
Chiti, F., & Dobson, C. M. (2006) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.75.101304.123901 · Cited by 6,435 · see citing works
Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide
Haass, C., & Selkoe, D. J. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2101 · Cited by 4,744 · see citing works
Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis
Kayed, R., Head, E., Thompson, J. L., McIntire, T. M., Milton, S. C., Cotman, C. W., & Glabe, C. G. (2003) · Science · doi:10.1126/science.1079469 · Cited by 4,064 · see citing works
Lee, V. M.-Y., Goedert, M., & Trojanowski, J. Q. (2001) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.24.1.1121 · Cited by 2,480 · see citing works
Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders
Ballatore, C., Lee, V. M.-Y., & Trojanowski, J. Q. (2007) · Nature Reviews Neuroscience · doi:10.1038/nrn2194 · Cited by 2,174 · see citing works
A Century of Alzheimer's Disease
Goedert, M., & Spillantini, M. G. (2006) · Science · doi:10.1126/science.1132814 · Cited by 2,106 · see citing works
Buée, L., Bussière, T., Buée‐Scherrer, V., Delacourte, A., & Hof, P. R. (2000) · Brain Research Reviews · doi:10.1016/s0165-0173(00)00019-9 · Cited by 2,007 · see citing works
von Bergen, M., Friedhoff, P., Biernat, J., Heberle, J., Mandelkow, E.-M., & Mandelkow, E. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.10.5129 · Cited by 1,021 · see citing works
Role of tau protein in both physiological and pathological conditions
AVILA, J., LUCAS, J. J., PÉREZ, M., & HERNÁNDEZ, F. (2004) · Physiological Reviews · doi:10.1152/physrev.00024.2003 · Cited by 1,005 · see citing works
Modulation of the dynamic instability of tubulin assembly by the microtubule-associated protein tau.
Drechsel, D. N., Hyman, A. A., Cobb, M. H., & Kirschner, M. W. (1992) · Molecular Biology of the Cell · doi:10.1091/mbc.3.10.1141 · Cited by 971 · see citing works
Probing the free-energy surface for protein folding with single-molecule fluorescence spectroscopy
Schuler, B., Lipman, E. A., & Eaton, W. A. (2002) · Nature · doi:10.1038/nature01060 · Cited by 921 · see citing works
Physical and chemical properties of purified tau factor and the role of tau in microtubule assembly
Cleveland, D. W., Hwo, S. Y., & Kirschner, M. W. (1977) · Journal of Molecular Biology · doi:10.1016/0022-2836(77)90214-5 · Cited by 881 · see citing works
Structural Classification of Toxic Amyloid Oligomers
Glabe, C. G. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.r800016200 · Cited by 783 · see citing works
Bertoncini, C. W., Jung, Y., Fernández, C. O., Hoyer, W., Griesinger, C., Jovin, T. M., & Zweckstetter, M. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0407146102 · Cited by 781 · see citing works
The interplay between structure and function in intrinsically unstructured proteins
Tompa, P. (2005) · FEBS Letters · doi:10.1016/j.febslet.2005.03.072 · Cited by 717 · see citing works
Intrinsic Disorder and Functional Proteomics
Predrag Radivojac, A., Iakoucheva, L. M., Oldfield, C. J., Zoran Obradovic, A., Uversky, V. N., & Dunker, A. K. (2006) · Biophysical Journal · doi:10.1529/biophysj.106.094045 · Cited by 705 · see citing works
Domains of tau Protein and Interactions with Microtubules
Gustke, N., Trinczek, B., Biernat, J., Mandelkow, E.-M., & Mandelkow, E. (1994) · Biochemistry · doi:10.1021/bi00198a017 · Cited by 655 · see citing works
Structural Polymorphism of 441-Residue Tau at Single Residue Resolution
Mukrasch, M. D., Bibow, S., Korukottu, J., Jeganathan, S., Biernat, J., Griesinger, C., Mandelkow, E., & Zweckstetter, M. (2009) · PLoS Biology · doi:10.1371/journal.pbio.1000034 · Cited by 652 · see citing works
Schweers, O., Schönbrunn, E., Marx, A., & Mandelkow�, E. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)51080-8 · Cited by 569 · see citing works
Common mechanisms of amyloid oligomer pathogenesis in degenerative disease
Glabe, C. G. (2006) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2005.04.017 · Cited by 569 · see citing works
Inhibition of Heparin-induced Tau Filament Formation by Phenothiazines, Polyphenols, and Porphyrins
Taniguchi, S., Suzuki, N., Masuda, M., Hisanaga, S., Iwatsubo, T., Goedert, M., & Hasegawa, M. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m408714200 · Cited by 542 · see citing works
Charge interactions can dominate the dimensions of intrinsically disordered proteins
Müller-Späth, S., Soranno, A., Hirschfeld, V., Hofmann, H., Rüegger, S., Reymond, L., Nettels, D., & Schuler, B. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1001743107 · Cited by 491 · see citing works
Global Hairpin Folding of Tau in Solution
Jeganathan, S., von Bergen, M., Brutlach, H., Steinhoff, H.-J., & Mandelkow, E. (2006) · Biochemistry · doi:10.1021/bi0521543 · Cited by 432 · see citing works
The Structural Basis of Monoclonal Antibody Alz50's Selectivity for Alzheimer's Disease Pathology
Carmel, G., Mager, E. M., Binder, L. I., & Kuret, J. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.51.32789 · Cited by 402 · see citing works
Friedhoff, P., Schneider, A., Mandelkow, E., & Mandelkow�, E. (1998) · Biochemistry · doi:10.1021/bi980537d · Cited by 401 · see citing works
Tau aggregation is driven by a transition from random coil to beta sheet structure.
von Bergen, M., Barghorn, S., Biernat, J., Mandelkow, E., & Mandelkow, E. (2005) · Biochimica et Biophysica Acta · doi:10.1016/j.bbadis.2004.09.010 · Cited by 376 · see citing works
(1997) · Europe PMC (PubMed Central) · Cited by 354 · see citing works
Barghorn, S., Zheng‐Fischhöfer, Q., Ackmann, M., Biernat, J., von Bergen�, M., Mandelkow�, E., & Mandelkow�, E. (2000) · Biochemistry · doi:10.1021/bi000850r · Cited by 351 · see citing works
Merchant, K. A., Best, R. B., Louis, J. M., Gopich, I. V., & Eaton, W. A. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0607097104 · Cited by 350 · see citing works
Toward a unified scheme for the aggregation of tau into Alzheimer paired helical filaments
Barghorn, S., & Mandelkow, E. (2002) · Biochemistry · doi:10.1021/bi026469j · Cited by 341 · see citing works
Mukhopadhyay, S., Krishnan, R., Lemke, E. A., Lindquist, S. L., & Deniz, A. A. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0611503104 · Cited by 316 · see citing works
Coil–globule transition in the denatured state of a small protein
Sherman, E., & Haran, G. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0601395103 · Cited by 294 · see citing works
Jeganathan, S., von Bergen, M., Mandelkow, E.-M., & Mandelkow, E. (2008) · Biochemistry · doi:10.1021/bi800783d · Cited by 286 · see citing works
Formation of Amyloid Fibers Triggered by Phosphatidylserine-Containing Membranes
Zhao, H., Tuominen, E. K. J., & Kinnunen, P. K. J. (2004) · Biochemistry · doi:10.1021/bi049002c · Cited by 273 · see citing works
Anionic Micelles and Vesicles Induce Tau Fibrillization in Vitro
Chirita, C. N., Necula, M., & Kuret, J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m301663200 · Cited by 244 · see citing works
Going new places using an old MAP: tau, microtubules and human neurodegenerative disease
Garcia, M. L., & Cleveland, D. W. (2001) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(00)00172-1 · Cited by 235 · see citing works
α-Synuclein Binds Large Unilamellar Vesicles as an Extended Helix
Trexler, A., & Rhoades, E. R. (2009) · Biochemistry · doi:10.1021/bi900114z · Cited by 212 · see citing works
Self-citationThe “Jaws” of the Tau-Microtubule Interaction
Mukrasch, M. D., von Bergen�, M., Biernat, J., Fischer, D., Griesinger, C., Mandelkow�, E., & Zweckstetter, M. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m607159200 · Cited by 196 · see citing works
Structural Impact of Heparin Binding to Full-Length Tau As Studied by NMR Spectroscopy
Sibille, N., Sillen, A., Leroy, A., Wieruszeski, J., Mulloy, B., Landrieu, I., & Lippens, G. M. (2006) · Biochemistry · doi:10.1021/bi060964o · Cited by 175 · see citing works
Triggers of Full-Length Tau Aggregation: A Role for Partially Folded Intermediates
Chirita, C. N., Congdon, E. E., Yin, H., & Kuret, J. (2005) · Biochemistry · doi:10.1021/bi0500123 · Cited by 166 · see citing works
Crowther, R. A., Olesen, O. F., Jakes, R., & Goedert, M. (1992) · FEBS Letters · doi:10.1016/0014-5793(92)81094-3 · Cited by 166 · see citing works
Surface-decoration of Microtubules by Human Tau
Santarella, R. A., Skiniotis, G., Goldie, K. N., Tittmann, P., Gross, H., Mandelkow, E., Mandelkow, E., & Hoenger, A. (2004) · Journal of Molecular Biology · doi:10.1016/j.jmb.2004.04.008 · Cited by 141 · see citing works
Sevcsik, E., Trexler, A., Dunn, J. M., & Rhoades, E. R. (2011) · Journal of the American Chemical Society · doi:10.1021/ja2009554 · Cited by 133 · see citing works
Self-citationThe Role of the Lipid Bilayer in Tau Aggregation
Elbaum‐Garfinkle, S., Ramlall, T. F., & Rhoades, E. R. (2010) · Biophysical Journal · doi:10.1016/j.bpj.2010.03.013 · Cited by 129 · see citing works
Self-citationPathways of tau fibrillization
Kuret, J., Chirita, C. N., Congdon, E. E., Kannanayakal, T. J., Li, G., Necula, M., Yin, H., & Zhong, Q. (2004) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2004.06.016 · Cited by 124 · see citing works
Single Molecule Characterization of α-Synuclein in Aggregation-Prone States
Trexler, A., & Rhoades, E. R. (2010) · Biophysical Journal · doi:10.1016/j.bpj.2010.08.056 · Cited by 116 · see citing works
Self-citationEvaluating triggers and enhancers of tau fibrillization
Kuret, J., Congdon, E. E., Li, G., Yin, H., Yu, X., & Zhong, Q. (2005) · Microscopy Research and Technique · doi:10.1002/jemt.20187 · Cited by 110 · see citing works
Eliezer, D., Barré, P., Kobašlija, M., Chan, D. K., Li, X., & Heend, L. (2004) · Biochemistry · doi:10.1021/bi048953n · Cited by 106 · see citing works
Quantitative Characterization of Heparin Binding to Tau Protein
Zhu, H., Fernández, C., Fan, J.-B., Shewmaker, F. P., Chen, J., Minton, A. P., & Liang, Y. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.035691 · Cited by 102 · see citing works
High throughput screening for small molecule inhibitors of heparin-induced tau fibril formation
Crowe, A., Ballatore, C., Hyde, E. G., Trojanowski, J. Q., & Lee, V. M. ‐. (2007) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2007.03.056 · Cited by 101 · see citing works
Crowther, T., Goedert, M., & Wischik, C. M. (1989) · Annals of Medicine · doi:10.3109/07853898909149199 · Cited by 100 · see citing works
O’Brien, E. P., Morrison, G., Brooks, B. R., et al. (2009) · The Journal of Chemical Physics · doi:10.1063/1.3082151 · Cited by 95 · see citing works
The Dynamic Structure of Filamentous Tau
Bibow, S., Mukrasch, M. D., Chinnathambi, S., Biernat, J., Griesinger, C., Mandelkow�, E., & Zweckstetter, M. (2011) · Angewandte Chemie International Edition · doi:10.1002/anie.201105493 · Cited by 94 · see citing works
von Bergen�, M., Barghorn, S., Jeganathan�, S., Mandelkow, E., & Mandelkow, E. (2006) · Neurodegenerative Diseases · doi:10.1159/000095257 · Cited by 68 · see citing works
Competing Interactions Stabilize Pro- and Anti-aggregant Conformations of Human Tau
Wegmann, S., Schöler, J., Bippes, C. A., Mandelkow�, E., & Müller, D. J. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.237875 · Cited by 48 · see citing works
Harbison, N. W., Bhattacharya, S., & Eliezer, D. (2012) · PLoS ONE · doi:10.1371/journal.pone.0034679 · Cited by 40 · see citing works
A Membrane‐Bound Antiparallel Dimer of Rat Islet Amyloid Polypeptide
Nath, A., Miranker, A. D., & Rhoades, E. R. (2011) · Angewandte Chemie International Edition · doi:10.1002/anie.201102887 · Cited by 39 · see citing works
Self-citationStructural consequences of an amino acid deletion in the B1 domain of protein G
O’Neil, K. T., Bach, A., & DeGrado, W. F. (2000) · Proteins Structure Function and Bioinformatics · doi:10.1002/1097-0134(20001115)41:3 · Cited by 11 · see citing works
Capila, I., & Linhardt, R. J. (2002) · Angewandte Chemie International Edition · doi:10.1002/1521-3773(20020201)41:3
Flagged first, then by citations
Research works printed but not linked: 2
- [24]Wilson DM Binder LI Am. J. Pathol 1997 150 2181 9176408 PMC1858305
- [56]Thirumalai D O’Brien EP Morrison G Brooks BR J. Chem. Phys 2009 130 PMC2736576 19334885
Cited by
Sorted by citations
Tau-based therapies in neurodegeneration: opportunities and challenges
Li, C., & Götz, J. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.155 · Cited by 272 · see citing works
Tau Internalization is Regulated by 6-O Sulfation on Heparan Sulfate Proteoglycans (HSPGs)
Rauch, J. N., Chen, J. J., Sorum, A. W., Miller, G. M., Sharf, T., See, S. K., Hsieh-Wilson, L. C., Kampmann, M., & Kosik, K. S. (2018) · Scientific Reports · doi:10.1038/s41598-018-24904-z · Cited by 211 · see citing works
Abyzov, A., Blackledge, M., & Zweckstetter, M. (2022) · Chemical Reviews · doi:10.1021/acs.chemrev.1c00774 · Cited by 215 · see citing works
Distinct Therapeutic Mechanisms of Tau Antibodies
Funk, K. E., Mirbaha, H., Jiang, H., Holtzman, D. M., & Diamond, M. I. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.657924 · Cited by 111 · see citing works
- Authors
- Elbaum-Garfinkle, S., & Rhoades, E.
- Affiliations
- Department of Molecular Biophysics and Biochemistry, Yale University, 266 Whitney Avenue, New Haven, Connecticut 06520-8114, United States
- Yale University (US)
- Corresponding author
- Rhoades, Elizabeth
- ORCID
- Rhoades, Elizabeth
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2012-10-01
- Volume
- 134
- Issue
- 40
- Pages
- 16607-16613
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- PMC
- PMC3477793
- OpenAlex
- W2004884414
- Cited by
- 149
- References
- 60
- Citations by year
- 2026: 9 · 2025: 6 · 2024: 5 · 2023: 11 · 2022: 10 · 2021: 15 · 2020: 11 · 2019: 19 · 2018: 14 · 2017: 12 · 2016: 7 · 2015: 9 · 2014: 11 · 2013: 8 · 2012: 2
- FWCI
- 6.44
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Journal of the American Chemical Society (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Science Foundation
- National Institutes of Health
- National Institute of General Medical Sciences (T32GM007223)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Keywords
- tau protein, protein aggregation, conformational ensembles, intrinsically disordered proteins, heparin binding, microtubule-binding domain, conformational intermediates, Alzheimer's disease, single-molecule FRET, long-range contacts, neurodegeneration
- MeSH terms
- Alzheimer Disease, Anticoagulants, Heparin, Humans, Protein Conformation, tau Proteins, Fluorescence Resonance Energy Transfer
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
