| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Raviv, Uri Wilson, Leslie Feinstein, Stuart C. Miller, Herbert P. Safinya, Cyrus R. Feinstein, H. Eric Chung, Peter J. Choi, Myung Chul Li, Youli |
| Description |
Author Affiliation: Chung PJ ( Materials Department, University of California, Santa Barbara, CA 93106); Choi MC ( Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea); Miller HP ( Molecular, Cellular, and Developmental Biology Department, University of California, Santa Barbara, CA 93106); Feinstein HE ( Molecular, Cellular, and Developmental Biology Department, University of California, Santa Barbara, CA 93106); Raviv U ( Institute of Chemistry, Hebrew University of Jerusalem, Jerusalem 91904, Israel); Li Y ( Materials Research Laboratory, University of California, Santa Barbara, CA 93106.); Wilson L ( Molecular, Cellular, and Developmental Biology Department, University of California, Santa Barbara, CA 93106); Feinstein SC ( Molecular, Cellular, and Developmental Biology Department, University of California, Santa Barbara, CA 93106); Safinya CR ( Materials Department, University of California, Santa Barbara, CA 93106); |
| Abstract |
Microtubules (MTs) are hollow cytoskeletal filaments assembled from ß-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 â ¼ 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 â ¼ 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. |
| ISSN |
00278424 |
| e-ISSN |
10916490 |
| Journal |
Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number |
47 |
| Volume Number |
112 |
| Language |
English |
| Publisher |
National Academy of Sciences |
| Publisher Date |
2015-11-01 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Biophysical Phenomena Microtubules Metabolism Tau Proteins Animals Models, Molecular Osmotic Pressure Protein Binding Protein Isoforms Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Multidisciplinary |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Multidisciplinary |
