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Final Report Summary - RAS:EFFECTORS (RAS superfamily and the interactions with their effectors: functional specificity)

Transformation by ras oncogenes induces the deregulation of intracellular signalling cascades that are critical elements in cell growth control. Ras genes code for small GTPases that act as GDP/ GTP-regulated molecular switches, that mediate cell proliferation, growth and development [1]. The signaling activity of Ras is dictated by a regulated GTPase cycle that modulates the conformation of Ras and its affinity for downstream effectors1[2]. Among those, Raf kinase, phosphoinositol-3 kinase and RalGDS are the ones best characterized [3, 4]; however the list continues to grow and more interactors have been reported to belong to the family of Ras effectors [5]. Although there is some structural data on these interactions, the physical characterization of these systems has been hampered by the relative instability and transient nature of such interactions.

1. Ras-Interactors from the RASOMICS database

- Objectives

As mentioned above, the list of Ras effectors has continued to grow and has provided the link between Ras activity and diverse biological responses.
Structural techniques have partly unraveled the Ras:effectors interaction mechanism. However, this set of protein-protein interactions is redundant and does not represent all partners. Possible Ras binding partners detected in vivo and reported in databases also span other protein families. So far, the studies carried out to rationalize the specificity of Ras proteins towards their effectors have been based only on the available set of Ras:effector crystal structures, ignoring the importance of protein flexibility.

- Work performed

In this work we extend the above to a large-scale bioinformatics and computational study, where we have carried out an extensive and massive driven-docking analysis for all the members of the Ras superfamily with those effectors for which no complex structure is available, but biological data supports complex formation. In this way we provide a broader picture of the Ras:effector association, which could then be used for extending the knowledge to other disciplines such as molecular biology or medicinal chemistry.
We are currently in the process of generating an open access knowledge-base resource focused on Ras superfamily and its effectors. This is meant to be an integrative approach in the line of wiki-like initiatives, where external knowledge will be can incorporated by other users as well.

- Results

For the sake of simplicity, we are describing here our findings only for the RasH interactors found through all the Protein-Protein Interaction (PPI) databases, grouped into several different categories according to the existence of specific domains along their sequence, thus creating functionally related groups (see Figure 1).

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