Disordered Motifs and Domains in Cell Control - October 11-15, 2014

Disordered Motifs and Domains in Cell Control

Sunday Speaker Abstracts

Signal Computation in Large Multi-protein Complexes Assembled on Mostly Disordered Platform Proteins Stephan Feller . Imm, Zamed; Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany. Receptor tyrosine kinases transmit signals through multi-protein complexes that contain large multi-site docking (LMD) proteins. The LMD proteins function as essential assembly platforms for sophisticated computational units in the cytoplasm of metazoan cells. Intensely studied examples of LMD proteins with critical roles in major cancers are the Gab family proteins Gab1 and Gab2. They display well-folded N-terminal pleckstrin homology (PH) domains, followed by long tail regions, which are supposedly entirely unstructured. How Gab proteins facilitate the computation of cross-talking pathways has remained a mystery. How is it possible that largely disordered proteins organize efficient, highly sophisticated signal computation units? The answer seems to be, that they may be not as ‘chaotic’ as previously thought. We have recently made two observations that challenge the idea of entirely intrinsically disordered Gab protein tails. Firstly, we have shown by biophysical methods that segments of the Gab tail regions can form helices (PPII, 3-10; Harkiolaki et al. 2009, Structure). Secondly, we have evidence from peptide array overlay blots and mutational studies that the long tail of the Gab1 protein can interact with the Gab1 PH domain at several sites (N-terminal folding nucleation [NFN] hypothesis; Simister et al. 2011, PLoS Biol). This should generate loop regions where functionally defined subcomplexes can assemble. When these subcomplexes then interact, cross-talk between multiple pathways can occur (Lewitzky et al. 2012, FEBS Lett). Interestingly, the helical tail segments serve as critically important docking sites for adaptors coupling the intracellular ‘nanocomputers’ to oncogenic receptors. They may thus be “Achilles’ heels” that could be targeted in human cancers. Uncoupling oncogenic receptors from their intracellular signalosomes should simultaneously affect several pathways, creating in essence a multi-potent inhibitor. Initial attempts to synthesise such new inhibitory compounds are under way.

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