Intrinsically Disordered Proteins and Regions: The Challenge to the Structure-Function Relationship

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Background

Proteins are fundamental molecules for life, as they carry out most of the biochemical function inside and outside cells. Much of our current understanding of protein biochemistry is founded on the sequence-structure-function relationship, whereby the amino acid sequence determines a specific folded 3D structure that in turn determines function and interactions of the protein. However, this view has increasingly been challenged during the last couple of decades, which witnessed a growing appreciation of the key role played by protein dynamics. In particular, it was discovered that a large portion of our proteome lacks a defined three-dimensional structure, while retaining function. This class of proteins are defined as Intrinsically Disordered Proteins (IDPs). A growing body of knowledge is emerging about the mechanism of folding of those IDPs, some of which populate a well-defined three-dimensional structure upon binding to their ligands, while others remain fundamentally unstructured even when bound to their physiological partners. In addition, it is known that many eucaryotic proteins alternate in their sequence stably folded parts and regions characterized by a high degree of dynamics, often called intrinsically disordered regions (IDRs). Examples of IDRs include loops or linkers, which can allosterically regulate protein function. IDPs and IDRs are involved in several fundamental physiological pathways in the eucaryotic cell, representing important pieces in the complicated puzzle of the molecular regulation of cellular functions. Finally, IDPs and IDRs are also involved in many human diseases, including cancer and neurodegeneration. For example, most proteins contained in the amyloid deposits characteristic of Alzheimer’s and Parkinson’s disease are disordered peptides and proteins.

Given the well-recognized link between protein disorder and biological function and misfunction, characterizing the dynamics of IDPs and IDRs is of fundamental importance in order to fully comprehend the mechanisms by how these proteins exert their functions. Relevant issues include understanding how and when IDPs adopt structure or remain disordered upon interaction with their ligands, the role of disordered linkers and loops in conformational dynamics and allostery, and the interplay between disorder, misfolding and disease-related protein aggregation. Because of the peculiarity and elusiveness of these protein systems, that lack of a defined structure, computational and experimental assessment of both the folding mechanism and the dynamics of IDPs is particularly challenging. On these bases, further experimental and/or computational data aimed to improve the understanding of these complex and elusive protein systems are demanded.

The aim of this Research Topic is to gather Original Research and Review Articles about the folding, function and misfunction of intrinsically disordered proteins and regions. Areas to be covered in this Research Topic may include:

• Biochemical and biophysical characterizations of IDPs binding/folding reactions
• Advances in Molecular Dynamic simulations to study IDPs and IDRs
• Characterization of functional role of disordered loops and linkers in globular proteins
• Integrated in vitro and in silico approaches to study protein disorder
• Links between protein dynamics and aggregation propensity
• The effect of mutations, in particular disease-related ones, on the dynamics and function of IDPs

Keywords: Structure-Function relationship, Intrinsically Disordered Proteins, Intrinsically Disordered Regions, Protein dynamics, Allostery

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