skip to content

Mutations and disease

It is not always possible to isolate important protein domains in sufficient quantity to study the biophysical properties of wild-type and mutant proteins. However by combining homology modelling and bioinformatics we have shown that by using well-characterised model proteins we can predict the effect of pathogenic mutations in Ig and FN domains. We have used these methods to look at the probable effects of pathogenic mutations in several other systems.

Pathogenic mutations in the L1 domain

Mutant L1 proteins have been assayed for localization with a cell and in binding assays. (A) localization of mutant proteins within CHO cells, compared with the effect of the same mutation on stability in the model Ig and fnIII domains. Mutations that decrease the stability of the model proteins by >1.5 kcal/mol are all related to proteins that fail to be expressed on the protein surface. Where ΔΔG <1.5 kcal/mol proteins are mostly trafficked with similar efficiency to wild type. (B) localization of proteins in COS-7 cells. Proteins were defined as being located on the surface "as wild type" or as being moderately or completely retained within the cell. Only mutants with a ΔΔG <1.5 kcal/mol are translocated as wild type.


Selected publications

  • Ma, L., Xu, M., Forman, J. R., Clarke, J. & Oberhauser, A. F. (2009). Naturally occurring mutations alter the stability of polycystin-1 PKD domains. J. Biol. Chem. 284, 32942-32949.
  • Randles, L. G., Lappalainen, I., Fowler, S. B., Moore, B., Hamill, S. J. & Clarke, J. (2006). Using model proteins to quantify the effects of pathogenic mutations in Ig-like proteins. J. Biol. Chem. 281, 24216-24226.
  • 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.