The importance of sequence diversity in the aggregation and evolution of proteins

Topic: Disease mechanisms in lab and animal studies

Incorrect folding of proteins, leading to aggregation and amyloid formation, is associated with a group of highly debilitating medical conditions including Alzheimer's disease and late-onset diabetes. The issue of how unwanted protein association is normally avoided in a living system is particularly significant in the context of the evolution of multidomain proteins, which account for over 70% of all eukaryotic proteins, where the effective local protein concentration in the vicinity of each domain is very high. Here we describe the aggregation kinetics of multidomain protein constructs of immunoglobulin domains and the ability of different homologous domains to aggregate together. We show that aggregation of these proteins is a specific process and that the efficiency of coaggregation between different domains decreases markedly with decreasing sequence identity. Thus, whereas immunoglobulin domains with more than about 70% identity are highly prone to coaggregation, those with less than 30-40% sequence identity do not detectably interact. A bioinformatics analysis of consecutive homologous domains in large multidomain proteins shows that such domains almost exclusively have sequence identities of less than 40%, in other words below the level at which coaggregation is likely to be efficient. We propose that such low sequence identities could have a crucial and general role in safeguarding proteins against misfolding and aggregation.

Key findings

• Incorrect folding of proteins, leading to aggregation and amyloid formation, is associated with a group of highly debilitating medical conditions including Alzheimer's disease and late-onset diabetes.
• The issue of how unwanted protein association is normally avoided in a living system is particularly significant in the context of the evolution of multidomain proteins, which account for over 70% of all eukaryotic proteins, where the effective local protein concentration in the vicinity of each domain is very high.

New to this subject? Start with our plain-English guide: Prevention →

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1038/nature04195
• PubMed: 16341018
• Original source →

Free copy unknown: no free-copy check has an answer for this record yet. That does not mean it is paywalled.

@article{wright2005-16341018,
  author  = {Wright, C. F. and Teichmann, S. A. and Clarke, J. and Dobson, C. M.},
  title   = {{The importance of sequence diversity in the aggregation and evolution of proteins}},
  journal = {Nature},
  year    = {2005},
  doi     = {10.1038/nature04195},
  pmid    = {16341018},
  url     = {https://doi.org/10.1038/nature04195}
}

Related studies in Prevention trials

• Lifespan evolution of neurocognitive impairment in schizophrenia - A narrative review Schizophrenia research. Cognition · 2022-01-20 · usefulness score 53/100
• Intersectin scaffold proteins and their role in cell signaling and endocytosis Biochimica et biophysica acta. Molecular cell research · 2016-10-12 · usefulness score 39/100
• Social participation diversity and cognitive trajectories in older adults with hypertension and diabetes: a longitudinal cohort study Research Square · 2026-10-12 · usefulness score 16/100
• Research attitudes mediate the association between educational attainment and willingness to participate in Alzheimer’s disease research beyond Alzheimer’s disease knowledge medRxiv · 2026-10-15 · usefulness score 16/100
• Mobile Clinics for Brain Health Equity: A Feasibility Study of Dementia Risk Reduction in Underserved Communities Research Square · 2026-09-30 · usefulness score 16/100
• Diagnostic Utility of Multi-Domain Language Measures Across the Alzheimer Disease Continuum medRxiv · 2026-09-29 · usefulness score 16/100

Similar studies

• AGGRESCAN: a server for the prediction and evaluation of "hot spots" of aggregation in polypeptides 2007 · How common it is
• The amyloid state and its association with protein misfolding diseases 2014 · Risk factors
• Protein Misfolding, Amyloid Formation, and Human Disease: A Summary of Progress Over the Last Decade 2017 · Risk factors
• Protein aggregation and aggregate toxicity: new insights into protein folding, misfolding diseases and biological evolution 2003 · Disease mechanisms
• Aggregation of Disordered Proteins Associated with Neurodegeneration 2023 · Brain tissue and pathology
• Rethinking neurodegeneration through a co-proteinopathy lens 2025 · Brain tissue and pathology

More on Prevention trials

• Newest in this subject Development and feasibility of a theory-driven multidomain intervention for community-dwelling older adults with mild cognitive impairment: a quasi-experimental pilot study based on the Multi-Theory Model Research Square · 2026-09-10 · Preprint — not yet peer-reviewed · usefulness score 16/100
• Newest in this subject Pre-dementia clinical trajectories associated with neuronal α-synuclein neuropathologic change: a retrospective cohort study Research Square · 2026-08-27 · Preprint — not yet peer-reviewed · usefulness score 16/100

See all studies in Prevention trials →