Transthyretin Aggregation under Partially Denaturing Conditions Is a Downhill Polymerization
- 14 May 2004
- journal article
- Published by American Chemical Society (ACS) in Biochemistry
- Vol. 43 (23), 7365-7381
- https://doi.org/10.1021/bi049621l
Abstract
The deposition of fibrils and amorphous aggregates of transthyretin (TTR) in patient tissues is a hallmark of TTR amyloid disease, but the molecular details of amyloidogenesis are poorly understood. Tetramer dissociation is typically rate-limiting for TTR amyloid fibril formation, so we have used a monomeric variant of TTR (M-TTR) to study the mechanism of aggregation. Amyloid formation is often considered to be a nucleation-dependent process, where fibril growth requires the formation of an oligomeric nucleus that is the highest energy species on the pathway. According to this model, the rate of fibril formation should be accelerated by the addition of preformed aggregates or “seeds”, which effectively bypasses the nucleation step. Herein, we demonstrate that M-TTR amyloidogenesis at low pH is a complex, multistep reaction whose kinetic behavior is incompatible with the expectations for a nucleation-dependent polymerization. M-TTR aggregation is not accelerated by seeding, and the dependence of the reaction timecourse is first-order on the M-TTR concentration, consistent either with a dimeric nucleus or with a nonnucleated process where each step is bimolecular and essentially irreversible. These studies suggest that amyloid formation by M-TTR under partially denaturing conditions is a downhill polymerization, in which the highest energy species is the native monomer. Our results emphasize the importance of therapeutic strategies that stabilize the TTR tetramer and may help to explain why more than eighty TTR variants are disease-associated. The differences between amyloid formation by M-TTR and other amyloidogenic peptides (such as amyloid β-peptide and islet amyloid polypeptide) demonstrate that these polypeptides do not share a common aggregation mechanism, at least under the conditions examined thus far.Keywords
This publication has 24 references indexed in Scilit:
- Assembly of Amyloid Protofibrils via Critical Oligomers—A Novel Pathway of Amyloid FormationJournal of Molecular Biology, 2002
- Transthyretin fibrillogenesis entails the assembly of monomers: a molecular model for in vitro assembled transthyretin amyloid-like fibrilsJournal of Molecular Biology, 2002
- Tetramer Dissociation and Monomer Partial Unfolding Precedes Protofibril Formation in Amyloidogenic Transthyretin VariantsPublished by Elsevier BV ,2001
- A comparative analysis of 23 structures of the amyloidogenic protein transthyretinJournal of Molecular Biology, 2000
- Review: TTR Amyloidosis—Structural Features Leading to Protein Aggregation and Their Implications on Therapeutic StrategiesJournal of Structural Biology, 2000
- Amyloid β-Protein FibrillogenesisPublished by Elsevier BV ,1997
- MODELS OF AMYLOID SEEDING IN ALZHEIMER'S DISEASE AND SCRAPIE: Mechanistic Truths and Physiological Consequences of the Time-Dependent Solubility of Amyloid ProteinsAnnual Review of Biochemistry, 1997
- Alternative conformations of amyloidogenic proteins govern their behaviorCurrent Opinion in Structural Biology, 1996
- Structure of prealbumin: Secondary, tertiary and quaternary interactions determined by Fourier refinement at 1.8 ÅJournal of Molecular Biology, 1978
- An X-ray study of the subunit structure of prealbuminJournal of Molecular Biology, 1971