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

Author

Listed:
  • Caroline F. Wright

    (University of Cambridge)

  • Sarah A. Teichmann

    (MRC Laboratory of Molecular Biology)

  • Jane Clarke

    (University of Cambridge, MRC Centre for Protein Engineering)

  • Christopher M. Dobson

    (University of Cambridge)

Abstract

Keeping proteins apart The tendency for proteins to aggregate is a problem that any living system must overcome. Conditions such as Alzheimer's disease and late-onset diabetes show what can happen if aggregation is not controlled. Two systems that suppress aggregation, molecular chaperones and quality control proteins, have been widely studied, but little is known about how selective pressure on amino acid sequences might contribute. A study of the giant molecule titin now shows that the sequences of multidomain proteins may have have evolved to reduce the probability of misfolding and aggregation. Titin is well suited to this study as its component immunoglobulin domains unfold and refold as an intrinsic part of muscle action. The results show that although equivalent immunoglobulin domains from different organisms frequently have around 95% sequence identity, sequence identity between adjacent domains in a given protein is only about 25%. Calculations suggest that neighbouring domain sequence identity over 30–40% could cause misfolding and unwanted inter-domain aggregation.

Suggested Citation

  • Caroline F. Wright & Sarah A. Teichmann & Jane Clarke & Christopher M. Dobson, 2005. "The importance of sequence diversity in the aggregation and evolution of proteins," Nature, Nature, vol. 438(7069), pages 878-881, December.
    • Handle: RePEc:nat:nature:v:438:y:2005:i:7069:d:10.1038_nature04195
    DOI: 10.1038/nature04195
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    Cited by:

    1. Chittibabu Guda & Brian R King & Lipika R Pal & Purnima Guda, 2009. "A Top-Down Approach to Infer and Compare Domain-Domain Interactions across Eight Model Organisms," PLOS ONE, Public Library of Science, vol. 4(3), pages 1-15, March.
    2. Ezequiel A Galpern & María I Freiberger & Diego U Ferreiro, 2020. "Large Ankyrin repeat proteins are formed with similar and energetically favorable units," PLOS ONE, Public Library of Science, vol. 15(6), pages 1-16, June.

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