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Protein aggregation

There are a number of options available to a polypeptide chain after synthesis, the most important of which is to fold to the native state. This is helped in vivo by cellular chaperones, which play a critical role: protecting the unfolded polypeptide chain from associating either with itself or which other proteins within the crowded cellular environment.

At any stage prior to formation of the native state of a gobular protein, exposure of hydrophobic residues that are normally buried can cause the protein to "aggregate". Most commonly these aggregates are disordered, amorphous assemblies of misfolded proteins, many of which are destroyed by the cellular machinery. However, significant accumulation of aggregates can be detrimental to health and can lead to deposition diseases such as Altzheimer's and Parkinson's.

Coaggregation of various protein domains with Titin I27

Coaggregation experiments of Titin I27. (a-c) The aggregation kinetics (black circles) fall between two limiting rates: I27 aggregating alone at 1 mg ml-1 (lower broken red line) and at 2 mg ml-1 (upper broken red line). (d) Aggregation rates from the coaggregation experiment normalized and fitted to a simple sigmoidal function (unbroken line).


Our research

In a landmark paper in Nature in 2005, we showed how the coaggregation of multidomain proteins is controlled by the sequence similarity between neighbouring domains. 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. We have also used a mutational strategy to show that several highly conserved residues in the fibronectin type III superfamily are conserved not for structure or function, but to prevent aggregation in multi-modular proteins.

We have continued our work on the amorphous aggregation of immunoglobulin domains, and have notes that the aggregation kinetics do not fit well to the standard models of protein aggregation. We hypothesise that the aggregation of these domains occurs from a misfolded dimeric species, leading to kinetic traces that are hyperbolic at long timescales.


Selected publications

  • Wright, C. F., Teichmann, S. A., Clarke, J. & Dobson, C. M. (2005). The importance of sequence diversity in the aggregation and evolution of proteins. Nature438, 878-881.
  • Steward, A., Adhya, S. & Clarke, J. (2002). Sequence conservation in Ig-like domains: The role of highly conserved proline residues in the fibronectin type III superfamily. J. Mol. Biol.318, 935-940.