Disordered protein segments: revisiting the structure-function paradigm
- Sophie Sacquin-Mora (Laboratoire de Biochimie Théorique, CNRS-UPR9080, France)
- Birthe Kragelund (University of Copenhagen, Denmark)
- Ben Schuler (University of Zurich, Switzerland)
- Elena Papaleo ( Danish Cancer Research Center, Denmark)
- Chantal Prevost (Laboratoire de Biochimie Theorique LBT - CNRS UPR 9080, France)
- Tâp Ha-Duong (BioCIS - Faculté de Pharmacie - Université Paris Sud, France)
Practical information : Applications for the workshop are now closed.
The workshop will start on tuesday october 3rd at 14:00 in the Hermite room in the Institut Poincaré (http://www.ihp.fr/), and will end at 12:00 on friday october 6th.
The structure-function relationship has represented a powerful paradigm for the study of macromolecules and their association for more than three decades. This resulted in impressive progress in the experimental and theoretical fields of macromolecular studies, and led to fundamental advances in our understanding of the factors that rule protein association, including the case of large conformational changes of folded protein regions. Yet, pioneering studies on intrinsically disordered proteins (IDP) or protein segments (IDS) have revealed that neither the organisation in structured folds nor the establishment of stable interactions are always necessary for association involving IDPs or IDSs to take place. These phenomenons are highly heterogeneous, ranging from stable interactions resulting from disorder to order transitions, to fuzzy interactions involving conformational ensembles or clouds. Furthermore, IDS-containing proteins can simultaneously present both stability, central to the structure-function paradigm, and the most extreme cases of disorder. Such situations are found for proteins containing disordered terminal segments or flexible loops or linkers. Linkers are essential agents of the ubiquitous modular reorganisation of protein domains upon binding, while disordered loops enable interface remodelling in response to a variety of partners. While this generally results in these segments presenting a stable structure in the complex, terminal protein segments can remain completely disordered even when the protein is embedded in large macromolecular assemblies like microtubules, protofibrils, recombinase nucleofilaments, etc... In all cases, the tails of the constitutive proteins, respectively tubulin, fibrinogen, or recombinase, are largely accessible within the superstructure. They are highly charged and play a fundamental part for aggregating associated proteins or even for the control of the superstructure assembly itself, in ways that escape the structure-function paradigm. For example, even though the tubulin C-terminal tails do not participate in tubulin-tubulin interfaces within microtubules, deleting these tails results in the aggregation of tubulin forming geometries like sheets or rings that differ from the biologically functional microtubules. An intermediate situation between disorder to order transition and completely disordered segments is encountered when specific binding motifs are embedded in disordered segments. The IDPs can then act as control moieties for network hubs.
Defining a new paradigm to understand the function of IDPs in the cell necessitates revisiting the way interactions are characterised and identifying relevant descriptors linked to function. The IDP community is progressing on this way, which requires integrating diverse scientific domains (physics, chemistry, biology and biochemistry, computation, bioinformatics), establishing new experimental and theoretical methods to investigate the IDP dynamics, defining new modelling protocols to efficiently explore the wide conformational space accessible to IDPs.
Disordered proteins (Intrinsically Disordered Proteins, IDPs) or protein segments (intrinsically disordered segment, IDSs) are now recognised as key players in the cell machinery, notably as mediator or modulator of macromolecule interactions or as signalling hubs. This opens a new area of research where the classical structure-function paradigm does not hold anymore. The purpose of this meeting is to push further our understanding of the role of disorder in biological processes, by bringing together IDP experts from various experimental and theoretical fields of research. For this 2017 edition, we will particularly focus our attention on the interplay between order and disorder, which can be found within single proteins (e.g. stably folded proteins presenting disordered loops, linkers or terminal tails) and can play prominent roles in mediating dynamic interactions, notably via the presence of binding motifs embedded in IDPs.
The following topics will be of particular interest to us.
- The sequence dependency of the IDSs dynamic behaviour; this includes the identification of relevant descriptors of the physicochemical and dynamics characteristics of IDPs that can be related to their sequence and interactions; tubulin constitutes a good working system to investigate sequence dependency as its isoforms essentially differ via the sequence of their disordered C-terminal tails; composition in tubulin isoforms differs according to the cell tissue and some isoforms are specifically responsible for resistance to anti mitotic agents.
Intramolecular interactions between folded protein regions and their disordered segments; interplay between intramolecular and intermolecular interactions; stable versus dynamic interactions; disordered protein segments may alternate between intra-inter-protein interactions when mediating protein assemblies: how can this phenomenon influence the aggregation process ?
- How do protein terminal tails control aggregation processes, leading to specific superstructure
architecture ? What are the roles of entropy and kinetics in the aggregation process ?
- The experimental characterisation of the dynamics of disordered protein segments; the identification of contact patterns between folded and disordered regions within a protein or between two proteic partners.
-The prediction of contact motifs via bioinformatics methods;
The development of theoretical methods to characterise IDSs disorder and to generate meaningful conformational ensembles for these systems. This question is being tackled by several leading groups who develop advanced algorithms specifically adapted to addressing IDP dynamics.
- The effect of ionic environment in modulating IDS interactions. Can the specific binding of ions favour disorder to order transitions ? Do ions explicitly participate to regulation processes together with IDRs ?
- Disordered segments as therapeutical targets; documented specificity of antimitotic drugs towards tubulin isoforms indicate that the disordered tails may constitute a target for new families of drugs.
The workshop will bring together experts from both experimental and theoretical fields of research and will favour extensive exchange between the participants during two poster sessions and a final round table summarising the workshop and opening new perspectives for the modelling of IDSs. In addition to the invited speakers talks, slots in the program are reserved for contributions from younger participants (students, postdocs or PIs) to be selected from submitted abstracts.
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2. Papaleo, E., et al., The Role of Protein Loops and Linkers in Conformational Dynamics and Allostery. Chem Rev, 2016. 116(11): p. 6391-423.
3. Tompa, P., Unstructural biology coming of age. Current Opinion in Structural Biology, 2011. 21(3): p. 419-25.