It is often the case that frequently occurring mutations can indicate the areas of functional importance within a protein. For example in Ras, a GTPase commonly mutated in cancer, most mutations occur around the GTPase domain, which is critical for the protein’s function (Reuter et al., 2000). In FLCN, no such domain has been identified, partly because the majority of mutations result in truncation or loss of the protein. In a recent study by Nahorski et al. (2011), missense and in-frame-deletion FLCN mutations were analysed to discover more information about the functionally important regions of the protein.
In silico evolutionary analysis found that the FLCN protein sequence evolved more slowly than the average gene and is under stronger purifying selection. This was especially true for the region between residue 100 and 230, suggesting an important function for this domain. Although this region does not bind FNIP1 or FNIP2, which both bind in the C-terminal, it may bind an as yet unidentified protein. Or it may be that this region is important to maintain the structure of FLCN, which is required for its function. Knowing the structure of FLCN would help to determine the role or significance of this well conserved region.
Eight missense and in-frame-deletion mutations, distributed throughout the FLCN gene, were analysed in this study. Of those 8 mutations, 6 were found to affect the stability of the FLCN protein, suggesting the mechanism of pathogenicity. The other 2 mutations had no effect on FLCN stability, its tumour suppressor activity or its localisation. One mutation has subsequently been found to be non-pathogenic and the other is still under investigation.
As FLCN mutations are found throughout the gene, it is likely that multiple domains contribute to both FLCN’s tumour suppressor activity and the protein’s stability. The authors of this study hypothesise that FLCN has multiple functions and that mutations which occur in BHD syndrome affect various aspects of FLCN’s function. It has already been seen that FLCN plays a role in multiple signalling networks but the full function of FLCN has yet to be determined.
- Nahorski MS, Reiman A, Lim DH, Nookala RK, Seabra L, Lu X, Fenton J, Boora U, Nordenskjöld M, Latif F, Hurst LD, Maher ER. (2011). Birt Hogg-Dubé syndrome associated FLCN mutations disrupt protein stability. Human Mutation DOI: 10.1002/humu.21519
- Reuter CW, Morgan MA, & Bergmann L (2000). Targeting the Ras signaling pathway: a rational, mechanism-based treatment for hematologic malignancies? Blood, 96 (5), 1655-69 PMID: 10961860