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Revealing Well-Defined Soluble States during Amyloid Fibril Formation by Multilinear Analysis of NMR Diffusion Data
journal contribution
posted on 2019-11-12, 20:40 authored by Kristine Steen Jensen, Sara Linse, Mathias Nilsson, Mikael Akke, Anders MalmendalAmyloid fibril formation is a hallmark
of neurodegenerative disease
caused by protein aggregation. Oligomeric protein states that arise
during the process of fibril formation often coexist with mature fibrils
and are known to cause cell death in disease model systems. Progress
in this field depends critically on development of analytical methods
that can provide information about the mechanisms and species involved
in oligomerization and fibril formation. Here, we demonstrate how
the powerful combination of diffusion NMR and multilinear data analysis
can efficiently disentangle the number of involved species, their
kinetic rates of formation or disappearance, spectral contributions,
and diffusion coefficients, even without prior knowledge of the time
evolution of the process or chemical shift assignments of the various
species. Using this method we identify oligomeric species that form
transiently during aggregation of human superoxide dismutase 1 (SOD1),
which is known to form misfolded aggregates in patients with amyotrophic
lateral sclerosis. Specifically, over a time course of 42 days, during
which SOD1 fibrils form, we detect the disappearance of the native
monomeric species, formation of a partially unfolded intermediate
in the dimer to tetramer size range, subsequent formation of a distinct
similarly sized species that dominates the final spectrum detected
by solution NMR, and concomitant appearance of small peptide fragments.
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multilinear data analysisRevealing Well-Defined Soluble Stateschemical shift assignmentsSOD 1 fibrils formfibril formationcause cell deathdisease model systemsAmyloid Fibril FormationspeciesOligomeric protein statesNMR Diffusion Data Amyloid fibril formationsuperoxide dismutase 1tetramer size rangeform misfolded aggregates
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