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Article

A Soluble Oligomer of Tau Associated with Fiber Formation Analyzed by NMR

Dylan W. Peterson^‡, Hongjun Zhou^§, Frederick W. Dahlquist^‡^§ and John Lew*^‡

Department of Molecular, Cellular and Developmental Biology and Department of Chemistry, University of California, Santa Barbara, Santa Barbara, California 93106

Biochemistry, 2008, 47 (28), pp 7393–7404

DOI: 10.1021/bi702466a

Publication Date (Web): June 18, 2008

‡

Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara.

Department of Chemistry, University of California, Santa Barbara.

* Address correspondence to this author. Tel: (805) 893-5336. Fax: (805) 893-4724. E-mail: lew@lifesci.ucsb.edu.

Abstract

Alzheimer’s disease (AD) is characterized by the intracellular accumulation of the neurofibrillary tangles comprised mainly of the microtubule-associated protein, tau. A critical aspect of understanding tangle formation is to understand the transition of soluble monomeric tau into mature fibrils by characterizing the structure of intermediates along the aggregation pathway. We have carried out multidimensional NMR studies on a C-terminal fragment of human tau (tau¹⁸⁷) to gain structural insight into the aggregation process. To specifically monitor intermolecular interaction between tau molecules in solution, we combined ¹⁵N- and ¹⁴N-labeled tau, the latter of which was modified with a paramagnetic nitroxide spin label (MTSL). Paramagnetic relaxation enhancement (PRE) of ¹⁵N-tau by interaction with MTSL-¹⁴N-tau allowed identification of low molecular weight oligomers of tau¹⁸⁷ that formed in response to heparin-induced aggregation. Two regions, VQIINK²⁸⁰ and VQIVYK³¹¹, were exclusively broadened by MTSL located at varied positions in the tau molecule. We propose that soluble oligomers of tau¹⁸⁷ are generated via intermolecular interactions at these motifs triggered by heparin addition. However, the associated line broadening at these motifs cannot be due to interaction between tau¹⁸⁷ and heparin directly. Instead, these specific interactions necessarily occur between tau molecules and are intermolecular in nature. Our data support the idea that VQIINK²⁸⁰ and VQIVYK³¹¹ are the major, if not sole, critical regions that directly mediate intermolecular contact between tau molecules during the early phases of aggregation.