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J Biol Chem. 2010 May 28;285(22):17137-47. doi: 10.1074/jbc.M110.117234. Epub 2010 Mar 24.

Stacked sets of parallel, in-register beta-strands of beta2-microglobulin in amyloid fibrils revealed by site-directed spin labeling and chemical labeling.

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Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom.


beta(2)-microglobulin (beta(2)m) is a 99-residue protein with an immunoglobulin fold that forms beta-sheet-rich amyloid fibrils in dialysis-related amyloidosis. Here the environment and accessibility of side chains within amyloid fibrils formed in vitro from beta(2)m with a long straight morphology are probed by site-directed spin labeling and accessibility to modification with N-ethyl maleimide using 19 site-specific cysteine variants. Continuous wave electron paramagnetic resonance spectroscopy of these fibrils reveals a core predominantly organized in a parallel, in-register arrangement, by contrast with other beta(2)m aggregates. A continuous array of parallel, in-register beta-strands involving most of the polypeptide sequence is inconsistent with the cryoelectron microscopy structure, which reveals an architecture based on subunit repeats. To reconcile these data, the number of spins in close proximity required to give rise to spin exchange was determined. Systematic studies of a model protein system indicated that juxtaposition of four spin labels is sufficient to generate exchange narrowing. Combined with information about side-chain mobility and accessibility, we propose that the amyloid fibrils of beta(2)m consist of about six beta(2)m monomers organized in stacks with a parallel, in-register array. The results suggest an organization more complex than the accordion-like beta-sandwich structure commonly proposed for amyloid fibrils.

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