The Ras/MAPK pathway transduces extracellular input in the form of growth factors and small molecules to the intracellular environment and its disregulation is one of the primary causes of cancer. More recently, a class of human genetic syndromes has emerged that are caused by germline mutations in several genes of this cascade. These disorders share overlapping characteristic features and an increased risk of developing cancer. Noonan, Costello, and CFC syndromes present common phenotypic features such as facial distortion, intellectual disabilities, and tumor predisposition. CFC affects the heart, has typical facial and skin features, mild to severe cognitive delays and feeding difficulties. At least four genes are directly linked to CFC: KRAS, BRAF, MEK1 and MEK2. Specific, single point mutations in at least one of these genes cause CFC syndrome. Unfortunately, there is currently no effective treatment for any of these syndromes. Our main goal is to study the molecular basis of CFC-causing mutations in MEK1 and their effect on the structure and interactions of the protein. Here we show a Molecular Dynamics study of three CFC-related MEK1 mutants (Y130C, E203K and Q56P). We show that these mutations tend to destabilize the important regulatory helix (31-73) of MEK1, which in turn increases the activity of this protein. The regulatory portion usually covers the core kinase domain, keeping its activity low. When the residues of the regulatory side or the matching one in the core side are mutated, their interaction is released and the kinase becomes more active. We also investigate in detail the differences in the structural impact of these three mutations on the MEK1 fold. We hope that this information will allow a better understanding of the basic dysfunction caused by MEK1 mutations that leads to this severe syndrome.
Dentici et al. Eur J Hum Genet. 2009 Jun;17(6):733-40
Fischmann et al Biochemistry. 2009 Mar 31;48(12):2661-74