STRUCTURAL CONFORMATIONS OF TAU PROTEIN IN SOLUTION & MEMBRANE-BOUND STATE

Cornell University, Ithaca NY

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Tau protein was initially identified as a microtubule assembly factor. Later research has shown that tau has diverse functionality and it is involved in signaling and cytosceletal organization [1]. Malfunctioning tau forms fibrilar inclusions and it was linked to several neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, some prion diseases. Neurodegenerative disorders with tau inclusions are known as taupaties [2]. Tau is expressed predominantly in the central and peripheral nervous system and, to the lesser extends, in kidney, lung, and testis. It is a large protein of more than 400 aa, which precise length and aa composition depends on the tau isoform. The protein can be subdivided into four regions: an N-terminal projection region, proline-rich domain, a microtubule-binding domain (MBD), and C-terminal region. Tau domains participate into binding of multiple partners, which is essential for the function. In solution, with no binding partner, tau has intrinsically disordered structure. However, NMR study on the MBD has shown some residual stricture, and it was proposed that these sites adopt a helical structure when bound to microtubules [3]. Later, the folding of the MBD into structure with high helical content in the presence of lipidic membranes was confirmed [4]. However, NMR spectroscopy experiences severe difficulties to assign the precise structure of MBD when bound to large lipidic objects due to very slow tumbling. Therefore, we undertook a pulsed dipolar (PDS) ESR study on the MBD of tau to elucidate the structural rearrangements that take place upon interaction of this domain with different membrane mimetics. One of the major advantages of PDS is its high potency to study structure/function events in membrane proteins. [1] M. Morris, S. Maeda, K. Vossel, and L. Mucke, (2011) Neuron 70, 410;[2] V. M. Lee, M. Goedert, J. Q. Trojanowski (2001), Ann. Rev Neurosci. 24, 1121;[3] D. Eliezer, P. Barre, M. Kobaslija, D. Chan, X. Li, and L. Heend (2005) Biochemistry 44, 1026;[4] P. Barre and D. Eliezer (2006), J. Mol. Biol. 362, 312.