Proline-Rich Region II (PRR2) Plays an Important Role in Tau–Glycan Interaction: An NMR Study
Anqesha Murray,
Lufeng Yan,
James M. Gibson,
Jian Liu,
David Eliezer,
Guy Lippens,
Fuming Zhang,
Robert J. Linhardt,
Jing Zhao,
Chunyu Wang
Affiliations
Anqesha Murray
Center for Biotechnology and Interdisciplinary Studies, Department of Chemistry and Chemical Biology, Departments of Biological Sciences, Rensselaer Polytechnic Institute, Troy, New York, NY 12180, USA
Lufeng Yan
Center for Biotechnology and Interdisciplinary Studies, Department of Chemistry and Chemical Biology, Departments of Biological Sciences, Rensselaer Polytechnic Institute, Troy, New York, NY 12180, USA
James M. Gibson
Center for Biotechnology and Interdisciplinary Studies, Department of Chemistry and Chemical Biology, Departments of Biological Sciences, Rensselaer Polytechnic Institute, Troy, New York, NY 12180, USA
Jian Liu
Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27514, USA
David Eliezer
Program in Structural Biology, Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA
Guy Lippens
Toulouse Biotechnology Institute, CNRS, INRA, INSA, University of Toulouse, 31077 Toulouse, France
Fuming Zhang
Center for Biotechnology and Interdisciplinary Studies, Department of Chemistry and Chemical Biology, Departments of Biological Sciences, Rensselaer Polytechnic Institute, Troy, New York, NY 12180, USA
Robert J. Linhardt
Center for Biotechnology and Interdisciplinary Studies, Department of Chemistry and Chemical Biology, Departments of Biological Sciences, Rensselaer Polytechnic Institute, Troy, New York, NY 12180, USA
Jing Zhao
Center for Biotechnology and Interdisciplinary Studies, Department of Chemistry and Chemical Biology, Departments of Biological Sciences, Rensselaer Polytechnic Institute, Troy, New York, NY 12180, USA
Chunyu Wang
Center for Biotechnology and Interdisciplinary Studies, Department of Chemistry and Chemical Biology, Departments of Biological Sciences, Rensselaer Polytechnic Institute, Troy, New York, NY 12180, USA
(1) Background: Prion-like transcellular spreading of tau pathology in Alzheimer’s disease (AD) is mediated by tau binding to the cell-surface glycan heparan sulfate (HS). However, the structural determinants for tau–HS interaction are not well understood. (2) Methods and Results: Binding-site mapping using NMR showed two major binding regions in full-length tau responsible for heparin interaction. Thus, two tau constructs, tau PRR2* and tau R2*, were designed to investigate the molecular details at the tau–heparin binding interface. The 2D 1H-15N HSQC of tau PRR2* and tau R2* lacked dispersion, which is characteristic for intrinsically disordered proteins. NMR titration of Arixtra into 15N-labeled tau R2* induced large chemical shift perturbations (CSPs) in 275VQIINK280 and downstream residues K281-D283, in which L282 and I278 displayed the largest shifts. NMR titration of Arixtra into 15N-labeled tau PRR2* induced the largest CSPs for residue R209 followed by residues S210 and R211. Residue-based CSP fitting showed that tau PRR2*–Arixtra interaction had a much stronger binding affinity (0.37–0.67 mM) than that of tau R2*–Arixtra (1.90–5.12 mM) interaction. (3) Conclusions: Our results suggested that PRR2 is a crucial domain for tau–heparin and tau–HS interaction.
