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Glycan Determinants of Heparin-Tau Interaction
- Source :
- Biophysical Journal, Biophysical Journal, Biophysical Society, 2017, 112 (5), pp.921-932. ⟨10.1016/j.bpj.2017.01.024⟩, Biophysical Journal, 2017, 112 (5), pp.921-932. ⟨10.1016/j.bpj.2017.01.024⟩
- Publication Year :
- 2017
- Publisher :
- Elsevier BV, 2017.
-
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 K-D of 0.2 and 70 mu M, 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.
- Subjects :
- Models, Molecular
0301 basic medicine
Glycan
Protein Conformation
Biophysics
tau Proteins
macromolecular substances
Plasma protein binding
nmr spectrometry
héparine
Sodium Chloride
Dermatan sulfate
heparinic acid
03 medical and health sciences
chemistry.chemical_compound
Protein structure
medicine
[SPI.GPROC]Engineering Sciences [physics]/Chemical and Process Engineering
Binding site
Surface plasmon resonance
Dose-Response Relationship, Drug
030102 biochemistry & molecular biology
biology
spectrométrie rmn
Heparin
Proteins
résonance plasmonique de surface
Nuclear magnetic resonance spectroscopy
Surface Plasmon Resonance
Peptide Fragments
3. Good health
maladie d'alzheimer
030104 developmental biology
chemistry
Biochemistry
biology.protein
[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Protein Binding
medicine.drug
Subjects
Details
- ISSN :
- 00063495 and 15420086
- Volume :
- 112
- Database :
- OpenAIRE
- Journal :
- Biophysical Journal
- Accession number :
- edsair.doi.dedup.....a81c283a0d7c3b4d5912d6463768123d