Structural Comparison of Human MAPKs Using Bioinformatics Tools

FABBRO, MONICA; BUSTAMANTE, JUAN PABLO; RODRÍGUEZ LIMARDO, RAMIRO; TURJANSKI, ADRIÁN GUSTAVO

Congreso; 4to Congreso Argentino de Bioinformática y Biología Computacional y 4ta Conferencia Internacional de la Sociedad Iberoamericana de Bioinformática (SoIBio); 2013

The Mitogen-Activated Protein Kinases (MAPKs) are a family of serine/threonine kinases that play an important role in transducing signals to the nucleus of the cell in response to external environmental changes. This signal transduction system, mediated by MAPKs, regulates key cellular functions such as proliferation, migration, apoptosis and cell differentiation. Perturbation of MAPK-regulated functions can result in different diseases including chronic inflammation and cancer. This is the reason why these proteins are widely studied and serve as molecular targets for the development of new antitumor drugs. Assuming that the function of proteins is coded in their structures, we decided to conduct a thorough analysis of the structural and dynamical properties of MAPKs to help understand their function. In humans, there are at least 11 members of the MAPK superfamily divided into six groups based on sequence similarity: 1. Extracellular signal-regulated kinases (ERKs): MAPK3 and MAPK1; 2. C-Jun N-terminal kinases (JNKs): MAPK8, MAPK9 and MAPK10; 3. P38 isoforms: MAPK11, MAPK12, MAPK13 and MAPK14; 4. ERK 4/5: MAPK7; 5. ERK3 (MAPK6) and ERK4 (MAPK4); 6. ERK7/8: MAPK15. Structural and biophysical features of MAPKs have been studied in great detail by many groups including our lab. MAPKs are structurally composed by two domains, an N-terminal domain formed largely by β-sheets and two helices, αC and αL16, and a C-terminal domain that it is mostly helical and has four shorts β-strands. In this work we used homology modeling technics to obtain the three-dimensional structures of nine of the MAPKs descripted in humans for which no structure has been solved. We then compared all the structures and determined residue structural conservation, stability contribution and flexibility for a better understanding of the MAPK fold.