The role of the lipid bilayer in tau aggregation.
Tau is a microtubule associated protein whose aggregation is implicated in a number of neurodegenerative diseases. We investigate the mechanism by which anionic lipid vesicles induce aggregation of tau in vitro using K18, a fragment of tau corresponding to the four repeats of the microtubule binding domain. Our results show that aggregation occurs when the amount of K18 bound to the lipid bilayer exceeds a critical surface density. The ratio of protein/lipid at the critical aggregation concentration is pH-dependent, as is the binding affinity. At low pH, where the protein binds with high affinity, the critical surface density is independent both of total lipid concentration as well as the fraction of anionic lipid present in the bilayer. Furthermore, the aggregates consist of both protein and vesicles and bind the beta-sheet specific dye, Thioflavin T, in the manner characteristic of pathological aggregates. Our results suggest that the lipid bilayer facilitates protein-protein interactions both by screening charges on the protein and by increasing the local protein concentration, resulting in rapid aggregation. Because anionic lipids are abundant in cellular membranes, these findings contribute to understanding tau-lipid bilayer interactions that may be relevant to disease pathology.
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, USA.
Shana
S
Elbaum-Garfinkle
Trudy
T
Ramlall
Elizabeth
E
Rhoades
D052160:Benzothiazoles; D005453:Fluorescence; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008051:Lipid Bilayers / Q000737:chemistry*; D010446:Peptide Fragments / Q000737:chemistry; D011485:Protein Binding; D055503:Protein Multimerization; D013050:Spectrometry, Fluorescence; D055672:Static Electricity; D013844:Thiazoles / Q000737:chemistry; D053835:Unilamellar Liposomes / Q000737:chemistry; D016875:tau Proteins / Q000737:chemistry*
D052160:Benzothiazoles; D008051:Lipid Bilayers; D010446:Peptide Fragments; D013844:Thiazoles; D053835:Unilamellar Liposomes; D016875:tau Proteins; C009462:thioflavin T