Interaction of Tau Protein with Model Lipid Membranes Induces Tau Structural Compaction and Membrane Disruption
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- 作者：Emmalee M. Jones ; Manish Dubey ; Phillip J. Camp ; Briana C. Vernon ; Jacek Biernat ; Eckhard Mandelkow ; Jaroslaw Majewski ; Eva Y. Chi
- 刊名：Biochemistry
- 出版年：2012
- 出版时间：March 27, 2012
- 年：2012
- 卷：51
- 期：12
- 页码：2539-2550
- 全文大小：503K
- 年卷期：v.51,no.12(March 27, 2012)
- ISSN：1520-4995
文摘
The misfolding and aggregation of the intrinsically disordered, microtubule-associated tau protein into neurofibrillary tangles is implicated in the pathogenesis of Alzheimer鈥檚 disease. However, the mechanisms of tau aggregation and toxicity remain unknown. Recent work has shown that anionic lipid membranes can induce tau aggregation and that membrane permeabilization may serve as a pathway by which protein aggregates exert toxicity, suggesting that the plasma membrane may play dual roles in tau pathology. This prompted our investigation to assess tau鈥檚 propensity to interact with membranes and to elucidate the mutually disruptive structural perturbations the interactions induce in both tau and the membrane. We show that although highly charged and soluble, the full-length tau (hTau40) is also highly surface active, selectively inserts into anionic DMPG lipid monolayers and induces membrane morphological changes. To resolve molecular-scale structural details of hTau40 associated with lipid membranes, X-ray and neutron scattering techniques are utilized. X-ray reflectivity indicates hTau40s presence underneath a DMPG monolayer and penetration into the lipid headgroups and tailgroups, whereas grazing incidence X-ray diffraction shows that hTau40 insertion disrupts lipid packing. Moreover, both air/water and DMPG lipid membrane interfaces induce the disordered hTau40 to partially adopt a more compact conformation with density similar to that of a folded protein. Neutron reflectivity shows that tau completely disrupts supported DMPG bilayers while leaving the neutral DPPC bilayer intact. Our results show that hTau40s strong interaction with anionic lipids induces tau structural compaction and membrane disruption, suggesting possible membrane-based mechanisms of tau aggregation and toxicity in neurodegenerative diseases.