TY  - JOUR
AU  - Jones, E. M.
AU  - Dubey, M.
AU  - Camp, P. J.
AU  - Vernon, B. C.
AU  - Biernat, J.
AU  - Mandelkow, E.
AU  - Majewski, J.
AU  - Chi, E. Y.
AU  - DESY
TI  - Interaction of Tau Protein with Model Lipid Membranes Induces Tau Structural Compaction and Membrane Disruption
JO  - Biochemistry
VL  - 51
SN  - 0006-2960
CY  - Columbus, Ohio
PB  - American Chemical Society
M1  - PHPPUBDB-23647
SP  - 2539
PY  - 2012
AB  - The misfolding and aggregation of the intrinsically disordered, microtubule-associated tau protein into neurofibrillary tangles is implicated in the pathogenesis of Alzheimer's 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's 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.
KW  - Cell Membrane: chemistry
KW  - Cell Membrane: metabolism
KW  - Humans
KW  - Lipid Bilayers: chemistry
KW  - Lipid Bilayers: metabolism
KW  - Neutron Diffraction
KW  - Protein Binding
KW  - Protein Conformation
KW  - Solubility
KW  - X-Ray Diffraction
KW  - tau Proteins: chemistry
KW  - tau Proteins: metabolism
KW  - Lipid Bilayers (NLM Chemicals)
KW  - tau Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:22401494
C2  - pmc:PMC3319454
UR  - <Go to ISI:>//WOS:000301946300018
DO  - DOI:10.1021/bi201857v
UR  - https://bib-pubdb1.desy.de/record/139102
ER  -