Direct force measurements reveal that protein Tau confers short-range attractions and isoform-dependent steric stabilization to microtubules
| Autor: | Cyrus R. Safinya, Youli Li, Herbert P. Miller, Uri Raviv, H. Eric Feinstein, Stuart C. Feinstein, Peter J. Chung, Leslie Wilson, Myung Chul Choi |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Steric effects
Gene isoform Models Molecular Aging 1.1 Normal biological development and functioning Tau protein tau Proteins Plasma protein binding Neurodegenerative Intrinsically disordered proteins Alzheimer's Disease Microtubules Biophysical Phenomena Microtubule Models Underpinning research Osmotic Pressure Acquired Cognitive Impairment Osmotic pressure 2.1 Biological and endogenous factors Animals Humans Protein Isoforms Aetiology Multidisciplinary biology Chemistry Small-angle X-ray scattering Neurosciences Molecular Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) SAXS force measurement Brain Disorders Crystallography PNAS Plus Biophysics biology.protein Dementia Cattle intrinsically disordered proteins Tau microtubule Protein Binding |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America, vol 112, iss 47 |
| Popis: | Microtubules (MTs) are hollow cytoskeletal filaments assembled from αβ-tubulin heterodimers. Tau, an unstructured protein found in neuronal axons, binds to MTs and regulates their dynamics. Aberrant Tau behavior is associated with neurodegenerative dementias, including Alzheimer's. Here, we report on a direct force measurement between paclitaxel-stabilized MTs coated with distinct Tau isoforms by synchrotron small-angle X-ray scattering (SAXS) of MT-Tau mixtures under osmotic pressure (P). In going from bare MTs to MTs with Tau coverage near the physiological submonolayer regime (Tau/tubulin-dimer molar ratio; ΦTau = 1/10), isoforms with longer N-terminal tails (NTTs) sterically stabilized MTs, preventing bundling up to PB ∼ 10,000-20,000 Pa, an order of magnitude larger than bare MTs. Tau with short NTTs showed little additional effect in suppressing the bundling pressure (PB ∼ 1,000-2,000 Pa) over the same range. Remarkably, the abrupt increase in PB observed for longer isoforms suggests a mushroom to brush transition occurring at 1/13 < ΦTau < 1/10, which corresponds to MT-bound Tau with NTTs that are considerably more extended than SAXS data for Tau in solution indicate. Modeling of Tau-mediated MT-MT interactions supports the hypothesis that longer NTTs transition to a polyelectrolyte brush at higher coverages. Higher pressures resulted in isoform-independent irreversible bundling because the polyampholytic nature of Tau leads to short-range attractions. These findings suggest an isoform-dependent biological role for regulation by Tau, with longer isoforms conferring MT steric stabilization against aggregation either with other biomacromolecules or into tight bundles, preventing loss of function in the crowded axon environment. |
| Databáze: | OpenAIRE |
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