title: Glycan Determinants of Heparin-Tau Interaction.
abstract: Tau aggregates into paired helical filaments within neurons, a pathological hallmark of Alzheimer's disease. Heparin promotes tau aggregation and recently has been shown to be involved in the cellular uptake of tau aggregates. Although the tau-heparin interaction has been extensively studied, little is known about the glycan determinants of this interaction. Here, we used surface plasmon resonance (SPR) and NMR spectroscopy to characterize the interaction between two tau fragments, K18 and K19, and several polysaccharides, including heparin, heparin oligosaccharides, chemically modified heparin, and related glycans. Using a heparin-immobilized chip, SPR revealed that tau K18 and K19 bind heparin with a KDof 0.2 and 70 μM, respectively. In SPR competition experiments, N-desulfation and 2-O-desulfation had no effect on heparin binding to K18, whereas 6-O-desulfation severely reduced binding, suggesting a critical role for 6-O-sulfation in the tau-heparin interaction. The tau-heparin interaction became stronger with longer-chain heparin oligosaccharides. As expected for an electrostatics-driven interaction, a moderate amount of salt (0.3 M NaCl) abolished binding. NMR showed the largest chemical-shift perturbation (CSP) in R2 in tau K18, which was absent in K19, revealing differential binding sites in K18 and K19 to heparin. Dermatan sulfate binding produced minimal CSP, whereas dermatan disulfate, with the additional 6-O-sulfo group, induced much larger CSP. 2-O-desulfated heparin induced much larger CSP in K18 than 6-O-desulfated heparin. Our data demonstrate a crucial role for the 6-O-sulfo group in the tau-heparin interaction, which to our knowledge has not been reported before.
authors.affiliation: College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China; Department of Chemistry and Chemical Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Centre National de La Recherche Scientifique-Unité Mixte de Recherche, Université de Lille 1, Villeneuve d'Ascq, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Huvent
authors.affiliation: Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés, University of Toulouse, CNRS, INRA, INSA, Toulouse, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Lippens
authors.affiliation: Department of Biochemistry, Program in Structural Biology, Weill Cornell Medical College, New York, New York.
authors.forename: David
authors.initials: D
authors.lastname: Eliezer
authors.affiliation: Department of Chemistry and Chemical Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York.
authors.forename: Anqiang
authors.initials: A
authors.lastname: Zhang
authors.affiliation: College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China.
authors.forename: Quanhong
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Chemical and Biological Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York.
authors.forename: Peter
authors.initials: P
authors.lastname: Tessier
authors.affiliation: Department of Chemistry and Chemical Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York; Department of Chemical and Biological Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York; Department of Biology and Biomedical Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Linhardt
authors.affiliation: Department of Chemistry and Chemical Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York. Electronic address: zhangf2@rpi.edu.
authors.forename: Fuming
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Chemistry and Chemical Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York; Department of Biological Sciences, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York. Electronic address: wangc5@rpi.edu.
authors.forename: Chunyu
authors.initials: C
authors.lastname: Wang
mesh_terms: D004305:Dose-Response Relationship, Drug; D006493:Heparin / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation; D012965:Sodium Chloride / Q000494:pharmacology; D020349:Surface Plasmon Resonance; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D010446:Peptide Fragments; D016875:tau Proteins; D012965:Sodium Chloride; D006493:Heparin