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

Disordered Motifs and Domains in Cell Control

Sunday Speaker Abstracts

Relating Conformational Flexibility to Cellular Function in Intrinsically Disordered Viral and Signalling Proteins Martin Blackledge 1 , Malene R. Jensen 1 , Rob W. Ruigrok 2 , Jaka Kragelj 1 , Robert Schneider 1 , Guillaume Communie 1 , Damien Maurin 1 , Sigrid Milles 1 , Guillaume Bouvignies 1 , Anton Abyzov 1 , Elise Delaforge 1 . 1 Institut de Biologie Structurale CEA-CNRS-UJF, Grenoble, France, 2 UVHCI UJF-CNRS, Grenoble, France. Proteins containing long (>50aa) intrinsically disordered regions (IDRs) comprise 50% of eukaryotic proteomes, and represent extreme examples where protein flexibility plays a determining role in function. The development of a meaningful molecular descriptions of IDRs remains a key challenge for contemporary structural biology. We have developed approaches to map the conformational energy landscape explored by IDRs using experimental NMR (1), providing calibrated procedures that make extensive use of cross-validation to test the predictive capacity of the resulting ensemble descriptions (2,3). We now use these tools to investigate the role of disorder in functional protein complexes involving IDRs. The study of protein-protein interactions involving IDRs poses a number of intriguing questions regarding recognition at the molecular level. Although few systems have been experimentally characterised, the structural plasticity of IDRs is thought to provide functional modes that are inaccessible to folded proteins. The replication machinery of paramyxoviruses represents a paradigm of IDP-mediated interactions, with the highly (>70%) disordered tetrameric Phosphoprotein initiating transcription and replication via its interaction with the disordered domain of the Nucleoprotein (4-6). Similarly the JNK signalling pathway exhibits extensive disorder, with specificity apparently controlled by disordered MAP kinase domains containing annotated linear motifs. In both cases post-translational modification plays a role in the functional interaction. In combination with the approaches outlined above, spin relaxation and chemical exchange measurements are used to characterize structure, dynamics and kinetics of these highly dynamic complexes in solution and in their native physiological environments.

1. Jensen et al Chem Rev In Press (2014) 2. Ozenne et al J.A.C.S. 134,15138 (2012) 3. Schwalbe et al Structure 22,238 (2014) 4. Jensen et al Proc. Natl. Acad. Sci. 108, 9839 (2011) 5. Jensen et Curr. Opin. Str. Biol. 23, 426 (2013) 6. Communie et al PLoS Pathogens 9, e1003631 (2013)

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