RAS:EFFECTORS · RAS superfamily and the interactions with their effectors: functional specificity
7РП — „Хора“ (Действия „Мария Кюри“)
- Период
- 2007-09-01 → 2009-08-31
- Финансиране от ЕС
- 30 000 €
- Участници
- 1
- Схема
- MC-ERG
Линиите свързват координатора с партньорите.
Накратко на български
Протеините от семейството Ras действат като молекулярни превключватели, които взаимодействат с различни партньори, например Raf киназата. Разбирането на тези взаимодействия помага да се разбере как се контролира растеят на клетките и защо при някои заболявания този процес се нарушава.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
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).
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
Ras genes code for small GTPases that act as GDP/GTP-regulated molecular switches. This exchange induces a conformational change that allows them to interact with their downstream effectors, and thus participate as central control elements in signal transduction. Mutated forms of the Ras oncoprotein are found in more than 30% of all human cancers, justifying the extensive research on them. Ras effectors have convergently developed a common subdomain in their unrelated overall structure for their interaction with Ras. Although detailed knowledge about the thermodynamics and dynamics of the interaction with Ras has accumulated, the molecular mechanism at atomic detail of effector activation and thus specificity is still elusive. Crystallographic, NMR, and other spectroscopic studies show that the flexibility of their so-called “switch regions” majorly contributes to the adaptability of the Ras proteins to their various partners, including disorder-to-order transitions upon binding to their partners, and “structural polymorphism” in their different complexes and in the unbound forms. This incorporates another degree of difficulty on the understanding of the Ras:effector association. Although some studies have been previously carried out in order to rationalize the specificity of the Ras proteins towards their different effectors, they have been based only in the availability of Ras:effector crystal structures and taking a rather static point of view. In this work we intend to extend this to a large-scale bioinformatics and computational study, including driven-docking of Ras proteins and their effectors for which no complex structure is available but biological data supports complex formation. In a further step, Molecular Dynamics simulations both on the unbound partners and on their complexes will yield information accounting both for the binding affinity and for the intrinsic plasticity crucial in the recognition and regulation of Ras pathways
Оригинален текст от CORDIS (на английски).
Участници
- FUNDACION SECTOR PUBLICO ESTATAL CENTRO NACIONAL INVESTIGACIONES ONCOLOGICAS CARLOS III · MadridКоординаторИспания
Връзки
Данни: CORDIS, © Европейски съюз