Biology; Chemistry and chemical biology; Chemical and biological engineering; Biomedical engineering
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3-O-sulfation of Heparan Sulfate Enhances Tau Interaction and Cellular Uptake, J. Zhao, Y. Zhu, X. Song, Y. Xiao, G. Su, X. Liu, Z. Wang, Y. Xu, J. Liu, D. Eliezer, T. F. Ramlall, G. Lippens, J. Gibson, F. Zhang, R. J. Linhardt, L. Wang, C. Wang, Angewandte Chemie Int. Ed., 59, 1818-1827, 2020.
Prion-like transcellular spreading of tau in Alzheimer's Disease (AD) is mediated by tau binding to cell surface heparan sulfate (HS). However, the structural determinants for tau-HS interaction are not well understood. Microarray and SPR assays of structurally defined HS oligosaccharides show that a rare 3-O-sulfation (3-O-S) of HS significantly enhances tau binding. In Hs3st1-/- (HS 3-O-sulfotransferase-1 knockout) cells, reduced 3-O-S levels of HS diminished both cell surface binding and internalization of tau. In a cell culture, the addition of a 3-O-S HS 12-mer reduced both tau cell surface binding and cellular uptake. NMR titrations mapped 3-O-S binding sites to the microtubule binding repeat 2 (R2) and proline-rich region 2 (PRR2) of tau. Tau is only the seventh protein currently known to recognize HS 3-O-sulfation. Our work demonstrates that this rare 3-O-sulfation enhances tau-HS binding and likely the transcellular spread of tau, providing a novel target for disease-modifying treatment of AD and other tauopathies.;
Angewandte Chemie Int. Ed., 59, 1818-1827; Note : if this item contains full text it may be a preprint, author manuscript, or a Gold OA copy that permits redistribution with a license such as CC BY. The final version is available through the publisher’s platform.
The Linhardt Research Labs.; The Shirley Ann Jackson, Ph.D. Center for Biotechnology and Interdisciplinary Studies (CBIS);
The Linhardt Research Labs Online Collection; Rensselaer Polytechnic Institute, Troy, NY; Angewandte Chemie - International Edition; https://harc.rpi.edu/;