Side Chain-dependent Stacking Modulates Tau Filament Structure

Martin Margittai,Ralf Langen

doi:10.1074/jbc.m605336200

Martin Margittai, Ralf Langen

Open Access

https://doi.org/10.1074/jbc.m605336200

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Abstract

The misfolding of proteins into highly ordered fibrils with similar physical properties is a hallmark of many degenerative diseases. Here, we use the microtubule associated protein tau as a model system to investigate the role of amino acid side chains in the formation of such fibrils. We identify a region (positions 272-289) in the tau protein that, in the fibrillar state, either forms part of a core of parallel, in-register, beta-strands, or remains unfolded. Single point mutations are sufficient to control this conformational switch with disease mutants G272V and DeltaK280 (found in familial forms of dementia) inducing a folded state. Through systematic mutagenesis we derive a propensity scale for individual amino acids to form fibrils with parallel, in-register, beta-strands. This scale should not only apply to tau fibrils but generally to all fibrils with same strand arrangement.

Highlights

Using site-directed spin labeling and electron paramagnetic resonance (EPR)2 spectroscopy, we recently showed that 18 consecutive residues in the third repeat and its N-terminal boundary were tightly packed and formed a parallel, in-register structure wherein same residues from different molecules came into contact [9]
The stacking of S3 remained unchanged. These results demonstrated that the G272V and ⌬K280 mutants had a pronounced impact on fibril structure, a feature that could contribute to the pathogenesis of these mutants in frontotemporal dementias
We examined the structure of S2 in the large isoform of tau (441 amino acids) and tested how its structure is affected by mutations

Summary

Introduction

We examine the role of side chain interactions and protein sequence in a parallel, in-register fibril and derive an experimental scale for the propensity of different amino acids to form parallel, in-register structures. Using site-directed spin labeling and electron paramagnetic resonance (EPR) spectroscopy, we recently showed that 18 consecutive residues (positions 303–320, referred to as S3) in the third repeat and its N-terminal boundary were tightly packed and formed a parallel, in-register structure wherein same residues from different molecules came into contact [9]. S2 can either form a separate domain of parallel, in-register structure or remain unfolded This marginal stability allowed us to assess the ability of different amino acids. Side Chain Stacking in Tau Filaments to form parallel-stacked structures, and to evaluate the roles of amino acid composition and sequence on tau fibril structure. Our findings are likely to be important for other fibrils with parallel, in-register structures

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