Presentation Type

Poster

Title of Abstract

Spatial Extent of Charge Repulsion Regulates Assembly Pathways for Lysozyme Amyloid Fibrils

Abstract

ABSTRACT

Formation of large protein fibrils with a cross b-sheet architecture is the key indicator for a wide variety of systemic and neurodegenerative diseases. Recent experiments have implicated oligomeric intermediates, transiently formed during fibril assembly, that are responsible for the cellular toxicity associated with amyloid diseases. Hence, elucidating the mechanisms that determine whether the aggregation of amyloidogenic proteins results in the formation of oligomers is directly relevant to our ability to control the toxic effects of amyloid fibril growth.

Using a combination of static and dynamic light scattering, atomic force microscopy, and circular dichroism, we find that amyloidogenic lysozyme monomers switch between three different assembly patterns: linear monomeric fibril assembly, linear oligomeric fibril assemblies and disordered precipitation. Fibril formation only occurred at salt concentrations that were sufficiently low to preserve net repulsion among the charged protein monomer. The switch to net attraction caused precipitation. The transition from monomeric to oligomeric fibril assembly occurred as salt-mediated charge screening reduced intramolecular repulsion among charged residues. To explain our observations, we suggest a model in which both intermolecular and intramolecular charge repulsion play a prominent role in ordered fibril assembly.

to appear in PLoS One (2011)

Categories

Engineering/Physical Science

Research Type

Course Related

Mentor Information

Dr. Martin Muschol

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Spatial Extent of Charge Repulsion Regulates Assembly Pathways for Lysozyme Amyloid Fibrils

ABSTRACT

Formation of large protein fibrils with a cross b-sheet architecture is the key indicator for a wide variety of systemic and neurodegenerative diseases. Recent experiments have implicated oligomeric intermediates, transiently formed during fibril assembly, that are responsible for the cellular toxicity associated with amyloid diseases. Hence, elucidating the mechanisms that determine whether the aggregation of amyloidogenic proteins results in the formation of oligomers is directly relevant to our ability to control the toxic effects of amyloid fibril growth.

Using a combination of static and dynamic light scattering, atomic force microscopy, and circular dichroism, we find that amyloidogenic lysozyme monomers switch between three different assembly patterns: linear monomeric fibril assembly, linear oligomeric fibril assemblies and disordered precipitation. Fibril formation only occurred at salt concentrations that were sufficiently low to preserve net repulsion among the charged protein monomer. The switch to net attraction caused precipitation. The transition from monomeric to oligomeric fibril assembly occurred as salt-mediated charge screening reduced intramolecular repulsion among charged residues. To explain our observations, we suggest a model in which both intermolecular and intramolecular charge repulsion play a prominent role in ordered fibril assembly.

to appear in PLoS One (2011)