Impact of ERK2 missense variants found in cancer: structural, function and stability experimental analysis

Proteins are the most versatile macromolecules in biosystems and serve crucial functions in essentially all biological processes. A reversible process important for the regulation in biological process is protein phosphorylation. Phosphorylation or dephosphorylation can affect the function of a protein in every conceivable way, increasing or suppressing activity, labelling a protein accessible for degradation, allowing it to move from one subcellular compartment to another, or enabling it to interact with or dissociate from other proteins. The abnormal phosphorylation of proteins is known to be a cause of major diseases, such as tumors. The progression of the neoplastic disease is generally driven by the accumulation of random genetic changes in cells and tissues, which can then develop independence from normal physiological controls due to randomly accumulating mutations. The most common genetic differences in the human genome are single nucleotide polymorphisms (SNPs), which are defined as single nucleotide variations (SNVs) occurring with a frequency of more than 1% in the population. These differences occur on average once every 300–400 base pairs, either in coding or in non-coding regions. SNVs may affect exon splicing or transcription, and are found more frequently than other types of genetic variations, such as differences in copy number, insertions, deletions, duplications, and rearrangements. SNVs in protein-coding regions have received the most attention, in spite of the fact that those regions account for only about 2% of the total human genome. SNVs in the coding region can be synonymous(sSNVs) if no amino acid change is produced, or non-synonymous(nsSNVs) if the substitution leads to a change in the protein sequence. The nsSNVs can be further divided into two categories: missense mutations, which lead to single amino acid changes, or nonsense mutations, which produce truncated or longer proteins. Missense mutations, that generate protein variants with a single amino acid variation (SAV), are of particular interest in biomedicine, since even just a single amino acid substitution may induce drastic structural alterations, which compromise the protein stability, or may induce crucial structural alterations able to perturb binding interfaces, to the point of impairing the protein function. In particular, this kind of approach seems to be relevant in cancer research considering that several somatic variants resulting from alterations at the amino acid level have been detected in cancer genome for several proteins. The single amino acid variations detected in the protein kinases and phosphatases, give rise to several of disorders and exert their effects by altering the phosphorylation states of intracellular proteins. The differences between protein kinase variants are at the basis of distinctive traits associated with the susceptibility to specific disease and/or drug response. Many compounds are now marked as ‘specific’ inhibitors of protein kinases, some of which have been used in literally hundreds of papers to study how a protein kinase is implicated in the regulation of a particular cellular event. Nevertheless, very few of these compounds are specific for the protein variants. The information resulting from the analysis of somatic mutations found in cancer tissues can improve the available therapies and create new and more specific ones, the personalized medicine.