Abstract
Ras GTPases are most prevalent proto-oncogenes in human cancer. Mutations in Ras remain untreatable more than three decades after the initial discovery. At the amino acid level, some residues under physical or functional constraints exhibit correlated mutations also known as coevolving/covariant residues. Revealing intra-molecular co-evolution between amino acid sites of proteins has become an emerging area of research as it enlightens the importance of variable regions. Here, I have identified and analyzed the coevolving residues in the Ras GTP binding domain (G-domain). The obtained covariant residue position data correlate well with the known experimental data on functionally important residues. Therefore, it is of interest to understand these residue co-variations for designing protein engineering experiments and target oncogenic Ras GTPases.
Highlights
Background: amino acid residues positions [7]
The Ras GTP binding domain amino acid relative to another is known as correlated mutation or (G-domain) functions as molecular switches regulating pathways co-evolution or co variation
An effector affect the evolution of certain other sites in the three dimensional molecule, GTPases-activating proteins (GAPs) stimulate the structure of the protein
Summary
Conserved residue positions are used to identify the functionally important sites in proteins, and a little attention has been given to the residues other than the conserved ones. It will be of interest to explore the role of correlated amino acid residues, which are located away (more than 5Å) from the GTP binding sites (Table 2). These residues are: T20, I21, R41, V45, I46, T50, E92, D93, H95, R98, E99, V103, K104, T124, P140, E153, T158, E162, and I163 (Figure 1 and Table 2). V29 position of Switch I and K104, located away from the pocket, (Figure 1A) showed Coevolutionary pattern with eight and seven other residue positions, respectively (Table 1 and Table 3). Coevolutionary pressure of eight and seven coevolving residue pairs associated with V29 and K104, respectively, indicate a larger role to be played by these positions, and opens up a question for future investigation
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