Identification of a novel microtubule binding and assembly domain in the developmentally regulated inter-repeat region of tau
Open accessAbstract
Tau is a developmentally regulated microtubule-associated protein that influences microtubule behavior by directly associating with tubulin. The carboxyl terminus of tau contains multiple 18-amino acid repeats that bind microtubules and are separated by 13-14-amino acid inter-repeat (IR) regions previously thought to function as "linkers." Here, we have performed a high resolution deletion analysis of tau and identified the IR region located between repeats 1 and 2 (the R1-R2 IR) as a unique microtubule binding site with more than twice the binding affinity of any individual repeat. Truncation analyses and site-directed mutagenesis reveal that the binding activity of this site is derived primarily from lys265 and lys272, with a lesser contribution from lys271. These results predict strong, discrete electrostatic interactions between the R1-R2 IR and tubulin, in contrast to the distributed array of weak interactions thought to underlie the association between 18-amino acid repeats and microtubules (Butner, K. A., and M. W. Kirschner. J. Cell Biol. 115:717-730). Moreover, competition assays suggest that the R1-R2 IR associates with microtubules at tubulin site(s) distinct from those bound by the repeats. Finally, a synthetic peptide corresponding to just 10 amino acids of the R1-R2 IR is sufficient to promote tubulin polymerization in a sequence-dependent manner. Since the R1-R2 IR is specifically expressed in adult tau, its action may underlie some of the developmental transitions observed in neuronal microtubule organization. We suggest that the R1-R2 IR may establish an adult-specific, high affinity anchor that tethers the otherwise mobile tau molecule to the tubulin lattice, thereby increasing microtubule stability. Moreover, the absence of R1-R2 IR expression during early development may allow for the cytoskeletal plasticity required of immature neurons.
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The N-terminal halves of each of Tau's four 18-residue aminoacid repeats bind to F-actin's hydrophobic pocket and fold into helical structure.
“In addition, the N-terminal halves of each of Tau’s four 18-residue aminoacid repeats64 bind to F-actin’s hydrophobic pocket and fold into helical structure (Fig. 3c; Supplementary Figs. 12 and 14).”
From Multivalent cross-linking of actin filaments and microtubules through the microtubule-associated protein Tau (2017) · cites this paper as [64]
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- Authors
- Goode, B., & Feinstein, S.
- Affiliations
- Neuroscience Research Institute, University of California, Santa Barbara 93106.
- Venue
- The Journal of cell biology
- Publisher
- Rockefeller University Press
- Published
- 1994-03-01
- Volume
- 124
- Issue
- 5
- Pages
- 769-782
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC2119949
- OpenAlex
- W2102701929
- Cited by
- 399
- References
- 5
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 10 · 2023: 11 · 2022: 6 · 2021: 6 · 2020: 10 · 2019: 20 · 2018: 15 · 2017: 13 · 2016: 10 · 2015: 14 · 2014: 15 · 2013: 8 · 2012: 16
- FWCI
- 9.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Cell Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- University of California, Santa Barbara
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Health Sciences › Medicine › Oncology › Cancer Treatment and Pharmacology
- Keywords
- tau protein, microtubule binding, microtubule-associated proteins, tubulin, lysine residues, electrostatic interactions, microtubule assembly, microtubule stability, neuronal development
- MeSH terms
- Aging, Amino Acid Sequence, Animals, Base Sequence, Binding Sites, Brain, Cattle, Cloning, Molecular, Kinetics, Microscopy, Electron, Microtubules, Models, Structural, Molecular Sequence Data, Recombinant Proteins, Repetitive Sequences, Nucleic Acid, Transcription, Genetic, Protein Biosynthesis, Tubulin, Polymerase Chain Reaction, Mutagenesis, Site-Directed, tau Proteins, Sequence Deletion, DNA Primers, DNA, Complementary, Rats
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