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3-O-Sulfation of Heparan Sulfate Enhances Tau Interaction and Cellular Uptake |
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| Authors: | Jing Zhao Yanan Zhu Xuehong Song Yuanyuan Xiao Guowei Su Xinyue Liu Zhangjie Wang Yongmei Xu Jian Liu David Eliezer Trudy F Ramlall Guy Lippens James Gibson Fuming Zhang Robert J Linhardt Lianchun Wang Chunyu Wang |
| Institution: | 1. Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, USA;2. Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, USA
These authors contributed equally to this work.;3. Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, USA;4. Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, USA;5. Department of Biochemistry, Program in Structural Biology, Weill Cornell Medical College, New York, NY, USA;6. Toulouse Biotechnology Institute, CNRS, INRA, INSA, University of Toulouse, 31077 Toulouse, France;7. Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, USA Department of Chemistry and Chemical Biology, Rensselaer Polytechnic Institute, Troy, NY, USA |
| Abstract: | 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. |
| Keywords: | Alzheimer-Krankheit Zelloberflächen Elektrostatische Wechselwirkungen Heparansulfat Proteine |