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Amyloid Fibril Formation by the Chain B Subunit of Monellin Occurs by a Nucleation-Dependent Polymerization Mechanism
journal contribution
posted on 2014-02-25, 00:00 authored by A. T. Sabareesan, Jayant B. UdgaonkarProteins
possessing very different structures, or even no structure,
form amyloid fibrils that are very similar in internal structure.
This suggests that the mechanisms by which amyloid fibrils form might
be very similar, irrespective of whether the fibrils are associated
with disease or with normal cellular function, or even if they have
no physiological importance. In this context, it is important to have
a model protein system whose amyloid fibril formation is robust in
its reproducibility, which can reveal the fundamentals of the amyloid
fibril reaction that may be applicable to all proteins. In this study,
the aggregation mechanism of amyloid fibril formation by chain B of
the heterodimeric protein monellin has been elucidated in detail.
It is shown that the aggregation reaction meets all the stringent
kinetic criteria of a homogeneous nucleation-dependent polymerization
mechanism, which is valid over a wide range of protein concentrations.
Quantitative analyses of the kinetic data using one approach based
on features of the entire kinetic curve, and another based on only
the initial rate of aggregation, indicate that the thermodynamic nucleus
is a dimer. Spherical oligomers are observed by atomic force microscopy
to form transiently early during fibril formation but are off-pathway
to the direct fibril formation pathway. It is shown that amyloid fibril
formation can be prevented by the addition of chain A of monellin
at early stages of chain B aggregation: the two free chains combine
to form native monellin, which leads to the dissociation of early
aggregates.
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Keywords
Chain B SubunitSpherical oligomersprotein concentrationsfibril formationMonellin Occursamyloid fibril formationforce microscopychain Bform amyloid fibrilsamyloid fibril reactionAmyloid Fibril Formationform transientlymodel protein systemfibril formation pathwayaggregation mechanismQuantitative analysesamyloid fibrils formaggregation reactionchain B aggregationheterodimeric protein monellin
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