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Biophys J. 2014 Sep 16;107(6):1441-52. doi: 10.1016/j.bpj.2014.07.046.

Tau binds to lipid membrane surfaces via short amphipathic helices located in its microtubule-binding repeats.

Author information

1
Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York; National Biomedical Center for Advanced ESR Technology, Cornell University, Ithaca, New York.
2
Department of Biochemistry, Weill Cornell Medical College, New York, New York; Program in Structural Biology, Weill Cornell Medical College, New York, New York.
3
Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York; National Biomedical Center for Advanced ESR Technology, Cornell University, Ithaca, New York. Electronic address: jhf3@cornell.edu.
4
Department of Biochemistry, Weill Cornell Medical College, New York, New York; Program in Structural Biology, Weill Cornell Medical College, New York, New York. Electronic address: dae2005@med.cornell.edu.

Abstract

Tau is a microtubule-associated protein that is genetically linked to dementia and linked to Alzheimer's disease via its presence in intraneuronal neurofibrillary tangle deposits, where it takes the form of aggregated paired helical and straight filaments. Although the precise mechanisms by which tau contributes to neurodegeneration remain unclear, tau aggregation is commonly considered to be a critical component of tau-mediated pathogenicity. Nevertheless, the context in which tau aggregation begins in vivo is unknown. Tau is enriched in membrane-rich neuronal structures such as axons and growth cones, and can interact with membranes both via intermediary proteins and directly via its microtubule-binding domain (MBD). Membranes efficiently facilitate tau aggregation in vitro, and may therefore provide a physiologically relevant context for nucleating tau aggregation in vivo. Furthermore, tau-membrane interactions may potentially play a role in tau's poorly understood normal physiological functions. Despite the potential importance of direct tau-membrane interactions for tau pathology and physiology, the structural mechanisms that underlie such interactions remain to be elucidated. Here, we employ electron spin resonance spectroscopy to investigate the secondary and long-range structural properties of the MBD of three-repeat tau isoforms when bound to lipid vesicles and membrane mimetics. We show that the membrane interactions of the tau MBD are mediated by short amphipathic helices formed within each of the MBD repeats in the membrane-bound state. To our knowledge, this is the first detailed elucidation of helical tau structure in the context of intact lipid bilayers. We further show, for the first time (to our knowledge), that these individual helical regions behave as independent membrane-binding sites linked by flexible connecting regions. These results represent the first (to our knowledge) detailed structural view of membrane-bound tau and provide insights into potential mechanisms for membrane-mediated tau aggregation. Furthermore, the results may have implications for the structural basis of tau-microtubule interactions and microtubule-mediated tau aggregation.

PMID:
25229151
PMCID:
PMC4167292
DOI:
10.1016/j.bpj.2014.07.046
[Indexed for MEDLINE]
Free PMC Article

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