Document Detail


Quantitative characterization of heparin binding to Tau protein: implication for inducer-mediated Tau filament formation.
MedLine Citation:
PMID:  19959468     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Neurofibrillary tangles, principally composed of bundles of filaments formed by the microtubule-associated protein Tau, are a hallmark of a group of neurodegenerative diseases such as Alzheimer disease. Polyanionic cofactors such as heparin can induce Tau filament formation in vitro. Here we quantitatively characterize the interaction between recombinant human Tau fragment Tau(244-372) and heparin (average molecular mass = 7 kDa) as well as heparin-induced fibril formation by using static light scattering, isothermal titration calorimetry, turbidity assays, and transmission electron microscopy. Our data clearly show that at physiological pH, heparin 7K, and human Tau(244-372) form a tight 1:1 complex with an equilibrium association constant exceeding 10(6) m(-1) under reducing conditions, triggering Tau fibrillization. In the absence of dithiothreitol, heparin shows a moderate binding affinity (10(5) m(-1)) to Tau(244-372), similarly triggering Tau fibrillization. Further fibrillization kinetics analyses show that the lag time appears to be approximately invariant up to a molar ratio of 2:1 and then increases at larger ratios of heparin/Tau. The maximum slope representing the apparent rate constant for fibril growth increases sharply with substoichiometric ratios of heparin/Tau and then decreases to some extent with ratios of >1:1. The retarding effect of heparin in excess is attributed to the large increase in ionic strength of the medium arising from free heparin. Together, these results suggest that the formation of the 1:1 complex of Tau monomer and heparin plays an important role in the inducer-mediated Tau filament formation, providing clues to understanding the pathogenesis of neurodegenerative diseases.
Authors:
Hai-Li Zhu; Cristina Fernández; Jun-Bao Fan; Frank Shewmaker; Jie Chen; Allen P Minton; Yi Liang
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't     Date:  2009-12-03
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  285     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2010 Feb 
Date Detail:
Created Date:  2010-02-01     Completed Date:  2010-04-09     Revised Date:  2011-07-25    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3592-9     Citation Subset:  IM    
Affiliation:
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
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MeSH Terms
Descriptor/Qualifier:
Algorithms
Calorimetry / methods
Heparin / chemistry*,  metabolism
Humans
Kinetics
Microscopy, Electron, Transmission
Models, Chemical
Molecular Weight
Neurofibrillary Tangles / chemistry*,  metabolism,  ultrastructure
Oxidation-Reduction
Peptide Fragments / chemistry*,  metabolism
Protein Binding
Recombinant Proteins / chemistry,  metabolism
tau Proteins / chemistry*,  genetics,  metabolism
Chemical
Reg. No./Substance:
0/Peptide Fragments; 0/Recombinant Proteins; 0/tau Proteins; 9005-49-6/Heparin
Comments/Corrections

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