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Partitioning conformational intermediates between competing refolding and aggregation pathways: Insights into transthyretin amyloid disease

Academic Article
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Overview

related to degree

  • Wiseman, R. Luke, Ph.D. in Chemistry, Scripps Research 2001 - 2005

authors

  • Wiseman, R. Luke
  • Powers, Evan
  • Kelly, Jeffery

publication date

  • 2005

journal

  • Biochemistry  Journal

abstract

  • Amyloid diseases are caused by the aberrant assembly of a protein in the extracellular space. Folded proteins are not amyloidogenic; however, the native state is generally in equilibrium with a minor population of unfolded or partially folded aggregation-competent conformers outside of the cell. Understanding how the partially unfolded conformers kinetically partition between the competing refolding and aggregation pathways provides insight into how misfolding, which occurs continuously, becomes pathogenic. Towards this end, we have previously studied the amyloidogenicity of transthyretin (TTR), a human beta-sheet-rich homotetrameric protein that must undergo rate-limiting tetramer dissociation and partial monomer unfolding to misassemble into amyloid and other aggregates. We demonstrate herein that TTR homotetramers reassemble by an unusual monomer-dimer-trimer-tetramer (MDRT) pathway. Therefore, the rate of every step in the reassembly pathway is dependent on the concentration of folded TTR monomer. Partitioning soluble TTR monomers between the reassembly pathway and the aggregation pathway should therefore depend on the relative concentrations of aggregates and assembly intermediates. Aggregate clearance is envisioned to play an important role in the partitioning of protein in vivo, where partitioning to the aggregation pathway becomes increasingly favorable under conditions where the concentration of aggregates is increased because aggregate clearance is slow relative to the rate of aggregation. This shift from efficient to inefficient aggregate clearance could occur with aging, offering an explanation for the age-associated nature of these neurodegenerative diseases.

subject areas

  • Amyloidosis
  • Biopolymers
  • Humans
  • Kinetics
  • Prealbumin
  • Protein Conformation
  • Protein Denaturation
  • Protein Folding
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Identity

PubMed Central ID

  • PMC2532856

International Standard Serial Number (ISSN)

  • 0006-2960

Digital Object Identifier (DOI)

  • 10.1021/bi0511484

PubMed ID

  • 16342952
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Additional Document Info

start page

  • 16612

end page

  • 16623

volume

  • 44

issue

  • 50

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