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

Abstract

Incorrect folding of proteins, leading to aggregation and amyloid formation, is associated with a group of highly debilitating medical conditions1,2 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 proteins3, 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.

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Figure 1: Aggregation of TI I27.
Figure 2: Analysis of the extent of coaggregation of different proteins with TI I27.
Figure 3: Analysis of sequence identities of immunoglobulin and fibronectin type III domains in the human genome.

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Acknowledgements

We thank K. Scott, A. Steward and J. Zurdo for clones; and R. Bader, D. Hall, C. Ponting and C. Chothia for discussions. This work was supported by the Wellcome Trust and the Leverhulme Trust (C.M.D.). C.F.W. held a Wellcome Trust prize studentship and J.C. is a Senior Wellcome Trust research fellow.

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Correspondence to Jane Clarke or Christopher M. Dobson.

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This file contains Supplementary Figures 1–5, Supplementary Tables 1–5 and additional references. (DOC 4082 kb)

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Wright, C., Teichmann, S., Clarke, J. et al. The importance of sequence diversity in the aggregation and evolution of proteins. Nature 438, 878–881 (2005). https://doi.org/10.1038/nature04195

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