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

Disordered Motifs and Domains in Cell Control

Monday Speaker Abstracts

Tinkering with Signaling: Evolution of Short Linear Motifs in Disordered Regions Alan Moses . University of Toronto, Toronto, Canada. Short linear motifs are a major class of functional elements commonly found in intrinsically disordered protein regions and are known to be important for transient signaling interactions. Evolutionary changes in these motifs could underlie differences in signaling and protein regulation between related species. We’ve been studying the patterns of evolution of short linear motifs in disordered regions, and I will describe two of our ongoing projects. First, we systematically identified short linear motifs that were present in single copy ancestral proteins, but were lost in one of the two paralogs after gene duplications. We find that short linear motifs are lost more often in paralogs than in single copy genes, suggesting that divergence of short linear motifs in disordered regions is a general mechanism for changes in function after gene duplications. Second, we serendipitously discovered a lineage-specific docking site in a highly conserved protein kinase. Taking advantage of this system, we have examined how new docking motifs appear in existing substrate proteins, and how new substrates are co-opted in this signaling network. This gives us a simple model for how signaling complexity increases during evolution. Control of Protein Localization to Microtubule Tips by Disordered Motifs Kai Jiang 1 , Grischa Toedt 2 , Norman E. Davey 2 , Susana Montenegro Gouveia 3 , Babet Van der Vaart 3 , Jeroen Demmers 4 , Michel O. Steinmetz 5 , Toby J. Gibson 2 , Anna Akhmanova 1 . 1 Utrecht University, Utrecht, Netherlands, 2 European Molecular Biology Laboratory, Heidelberg, Germany, 3 Erasmus Medical Center, Rotterdam, Netherlands, 4 Erasmus Medical Center, Rotterdam, Netherlands, 5 Paul Scherrer Institut, Villigen PSI, Switzerland. Growing microtubule ends are associated with a large variety of proteins, known as +TIPs (plus end tracking proteins), which connect microtubules to different cellular structures and regulate microtubule dynamics. The core components of the +TIP network are the members of the End Binding (EB) family, which can autonomously recognize growing microtubule ends and recruit to them numerous, structurally diverse factors. A large group of +TIPs bind to EB proteins through natively unstructured basic and serine-rich polypeptide regions containing a short core motif SxIP (serine-any amino acid-isoleucine-proline). We have performed a proteome-wide search for mammalian SxIP-containing +TIPs by combining biochemical and bioinformatics approaches and identified a set of EB partners that have the capacity to accumulate at the growing microtubule ends, including protein kinases, a small GTPase, membrane- and actin- associated proteins. Proteome-wide analysis of EB partners showed that the SxIP motif is the major microtubule tip localization signal. The knowledge of the properties of this motif made it possible to address the function of microtubule plus end association in different proteins. Our study demonstrates that disordered motifs are key players in the highly complex +TIP interactome. The approaches used in our study can be applied to many other classes of protein motifs to discover their proteome-wide occurrence and their contribution to the global protein interaction networks.

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