Probing Protein Conformational Plasticity

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Background

Intrinsically disordered proteins (IDPs) can adopt alternative amyloid-prone topologies in solution or in biomolecular condensates to promote the assembly of β-rich amyloid structures in health and disease. How these amyloid-prone conformations are formed and stabilized to promote prion-like behavior remains largely unsolved. It is also unclear as to how cofactor binding, including cellular metabolites and molecular chaperones, influence these conformational transitions. IDPs often contain low-complexity regions and exist as ensembles of conformations that pose significant challenges for their structural characterization, particularly in the detection of weakly populated states that might be compatible with amyloid assembly or biomolecular condensate formation. With the advent of artificial intelligence-based protein structure prediction algorithms, such as AlphaFold (DeepMind), and their ability to accurately predict the structure of folded proteins, the next obvious challenge is now set: what is needed to predict the conformational ensemble of disordered proteins and their prion-like structural conversions?

Recent mechanistic advances in liquid-liquid phase separation and amyloid assembly have detailed the key structural determinants that dictate condensate and amyloid formation. However, although IDPs may acquire ordered structures in dense phases, this gain in ordered structure is often undetected in structural studies. Therefore, the transitions from the conformations adopted in solution by disordered proteins to the β-rich amyloids are still to be described in detail. Describing the nascent pro-amyloid structures would enable us to determine if the transitions triggering amyloid-like aggregation are encoded within low-complexity sequences, providing the basis for creating predictors of structural plasticity upon confinement. The role of post-translational modifications or cofactor binding as switches of these putative recognition elements encoded in the sequence may be key to understanding the structural basis of amyloid aggregation in health and disease. Scarcity in the knowledge of the conformational ensembles gathered by disordered proteins constitutes a bottleneck for the accurate prediction of functional elements that may experience structural plasticity. Solving these queries, as challenging as they may be, would enable us to construe the molecular mechanisms of protein misfolding diseases and to externally modulate prion-like protein conformations. An integrative approach is necessary to build next-generation predictors for proteins showing conformational plasticity in human diseases.

We encourage submissions using diverse methodologies to probe protein conformational plasticity. Both original articles and reviews are welcome. Submissions may cover topics related to the following themes:

• Structural transitions in proteins within crowded environments (e.g. biomolecular condensates)
• How does local folding contribute to multivalent biomolecular interactions?
• Are amyloid-prone conformations present in minor populations in the conformational ensemble?
• Which conformational transitions govern primary and secondary nucleation of amyloid?
• How do structural transitions determine the pathways to alternative fibril morphs and amyloid oligomers?

Keywords: Protein conformational transitions, AlphaFold, metastable folding intermediates, protein ensemble, structural predictions

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