ArticleJournal of the American Chemical Society2013
A mechanistic model for amorphous protein aggregation of immunoglobulin-like domains.
Article in Journal of the American Chemical Society, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed.
- Chaperone BiP controls ER stress sensor Ire1 through interactions with its oligomers.Life science alliance · 2024Article
- Chemical Modification of the Amino Groups of Human Insulin: Investigating Structural Properties and Amorphous Aggregation of Acetylated Species.The protein journal · 2023Article
- Global analysis of kinetics reveals the role of secondary nucleation in recombinant spider silk self-assembly.Protein science : a publication of the Protein Society · 2023Article
- Article
- Aggregation Time Machine: A Platform for the Prediction and Optimization of Long-Term Antibody Stability Using Short-Term Kinetic Analysis.Journal of medicinal chemistry · 2022Article
- Long-term stability predictions of therapeutic monoclonal antibodies in solution using Arrhenius-based kinetics.Scientific reports · 2021Article
- The Protein Folding Problem: The Role of Theory.Journal of molecular biology · 2021Review
- A quantitative calcium phosphate nanocluster model of the casein micelle: the average size, size distribution and surface properties.European biophysics journal : EBJ · 2021Article
- Rationalizing the Role of Monosodium Glutamate in the Protein Aggregation Through Biophysical Approaches: Potential Impact on Neurodegeneration.Frontiers in neuroscience · 2021Review
- Folding pathway of an Ig domain is conserved on and off the ribosome.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Light induces oxidative damage and protein stability in the fungal photoreceptor Vivid.PloS one · 2018Article
- Factors affecting the physical stability (aggregation) of peptide therapeutics.Interface focus · 2017Review
- An Internal Disulfide Locks a Misfolded Aggregation-prone Intermediate in Cataract-linked Mutants of Human γD-Crystallin.The Journal of biological chemistry · 2016Article
- Experimental Model System to Study pH Shift-Induced Aggregation of Monoclonal Antibodies Under Controlled Conditions.Pharmaceutical research · 2016Article
- Measurement of amyloid formation by turbidity assay-seeing through the cloud.Biophysical reviews · 2016Review
- Transient misfolding dominates multidomain protein folding.Nature communications · 2015Article
- Mechanism of initiation of aggregation of p53 revealed by Φ-value analysis.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- Free energy landscapes for initiation and branching of protein aggregation.Proceedings of the National Academy of Sciences of the United States of America · 2013Article
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Authors and funding
4 authors.
Funding
Abstract
Protein aggregation is associated with many debilitating diseases including Alzheimer's, Parkinson's, and light-chain amyloidosis (AL). Additionally, such aggregation is a major problem in an industrial setting where antibody therapeutics often require high local concentrations of protein domains to be stable for substantial periods of time. However, despite a plethora of research in this field, dating back over 50 years, there is still no consensus on the mechanistic basis for protein aggregation. Here we use experimental data to derive a mechanistic model that well describes the aggregation of Titin I27, an immunoglobulin-like domain. Importantly, we find that models that are suitable for nucleated fibril formation do not fit our aggregation data. Instead, we show that aggregation proceeds via the addition of activated dimers, and that the rate of aggregation is dependent on the surface area of the aggregate. Moreover, we suggest that the "lag time" seen in these studies is not the time needed for a nucleation event to occur, but rather it is the time taken for the concentration of activated dimers to cross a particular solubility limit. These findings are reminiscent of the Finke-Watzky aggregation mechanism, originally based on nanocluster formation and suggest that amorphous aggregation processes may require mechanistic schemes that are substantially different from those of linear fibril formation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.