Disordered Motifs and Domains in Cell Control - October 11-15, 2014 - page 23

Disordered Motifs and Domains in Cell Control Sunday Speaker Abstracts
Relating Conformational Flexibility to Cellular Function in Intrinsically Disordered Viral
and Signalling Proteins
Martin Blackledge1, Malene R. Jensen1, Rob W. Ruigrok2, Jaka Kragelj 1, Robert Schneider1,
Guillaume Communie1, Damien Maurin1, Sigrid Milles1, Guillaume Bouvignies 1, Anton
Abyzov1, Elise Delaforge1.
1Institut de Biologie Structurale CEA-CNRS-UJF, Grenoble, France, 2UVHCI 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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