Ricerc@Sapienza

A key step in cellular signaling pathways is the reversible phosphorylation of proteins. Metabolism, cell growth and differentiation, proliferation and apoptosis, cytoskeletal rearrangement and angiogenesis, are controlled by reversible phosphorylation. This process is mediated by the action of protein kinases that catalyze the transfer of a phosphate group from ATP or GTP to lipids or proteins. The phosphate acceptor in proteins is the hydroxyl group of either a serine, threonine, or tyrosine residue. The acceptor residues can be on the same protein kinase, as in the case of autophosphorylation, or on different protein targets. The human kinome contains 518 protein kinases and approximately 20 lipid kinases that comprise 1.7% of human genes. The pivotal role of kinases in disease pathophysiology is evident by the observation that kinases mutation lead to alteration in cellular signalling then leading to different pathologies, ranging from diabetes, to cancer, cardiovascular and neurodegenerative or immunological disorders. Particularly, in cancer tissues, has been reported the expressions of several single residue variants (SRV) of kinases caused by non synonymous single nucleotide polymorphisms (nsSNPs) that occurr in the DNA coding region and encode a change in the amino acid sequence. The single amino acid substitution can potentially affect the protein structure-function relationships in different ways, such as changes in protein function, stability, flexibility and interaction with other proteins, nucleic acids, and other molecules. The aim of this project is the study of some natural SRVs of MAPKs, in particular MAPK1. In this study we will select some natural SRV of MAPK1 that are expressed in cancer tissues and reported in cancer databases. These variants will be characterized to investigate the effect of single amino acid substitution on MAPK1 thermal and thermodynamic stability and structure in solution.