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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