Exon-phase symmetry and intrinsic structural disorder promote modular evolution in the human genome

A key signature of module exchange in the genome is phase symmetry of exons, suggestive of exon shuffling events that occurred without disrupting translation reading frame. At the protein level, intrinsic structural disorder may be another key element because disordered regions often serve as functional elements that can be effectively integrated into a protein structure. Therefore, we asked whether exon-phase symmetry in the human genome and structural disorder in the human proteome are connected, signalling such evolutionary mechanisms in the assembly of multi-exon genes. We found an elevated level of structural disorder of regions encoded by symmetric exons and a preferred symmetry of exons encoding for mostly disordered regions (>70% predicted disorder). Alternatively spliced symmetric exons tend to correspond to the most disordered regions. The genes of mostly disordered proteins (>70% predicted disorder) tend to be assembled from symmetric exons, which often arise by internal tandem duplications. Preponderance of certain types of short motifs (e.g. SH3-binding motif) and domains (e.g. high-mobility group domains) suggests that certain disordered modules have been particularly effective in exon-shuffling events. Our observations suggest that structural disorder has facilitated modular assembly of complex genes in evolution of the human genome. © 2013 The Author(s)

The Melting Diagram of Protein Solutions and Its Thermodynamic Interpretation

Here we present a novel method for the characterization of the hydration of protein solutions based on measuring and evaluating two-component wide-line 1H NMR signals. We also provide a description of key elements of the procedure conceived for the thermodynamic interpretation of such results. These interdependent experimental and theoretical treatments provide direct experimental insight into the potential energy surface of proteins. The utility of our approach is demonstrated through the examples of two proteins of distinct structural classes: the globular, structured ubiquitin; and the intrinsically disordered ERD10 (early response to dehydration 10). We provide a detailed analysis and interpretation of data recorded earlier by cooling and slowly warming the protein solutions through thermal equilibrium states. We introduce and use order parameters that can be thus derived to characterize the distribution of potential energy barriers inhibiting the movement of water molecules bound to the surface of the protein. Our results enable a quantitative description of the ratio of ordered and disordered parts of proteins, and of the energy relations of protein–water bonds in aqueous solutions of the proteins

Intrinsic structural disorder in cytoskeletal proteins.

Cytoskeleton, the internal scaffold of the cell, displays an exceptional combination of stability and dynamics. It is composed of three major filamentous networks, microfilaments (actin filaments), intermediate filaments (neurofilaments), and microtubules. Together, they ensure the physical and structural stability of the cell, whereby also mediating its large-scale structural rearrangements, motility, stress response, division, and internal transport. All three cytoskeletal systems are built upon the same basic design: they have a central repetitive scaffold assembled from folded building elements, surrounded and regulated by accessory regions/proteins that regulate its formation and mediate its countless interactions with its environment, serving to send regulatory signals to and from the cytoskeleton. Here, we elaborate on the idea that the opposing features of stability and dynamics are also manifest in the dichotomy of the structural status of its components, the core being highly structured and the accessory proteins/regions being highly disordered, and are responsible for most of the regulatory (post-translational) input promoting adaptive responses and providing dynamics necessary for each of the cytoskeletal systems. This pattern entails special consequences, in which the manifold functional advantages of structural disorder, most pronounced in regulatory and signaling functions, are all exploited by nature. (c) 2013 Wiley Periodicals, Inc

Multisteric regulation by structural disorder in modular signaling proteins: An extension of the concept of allostery

Allostery is a classical regulatory mechanism of proteins in which a signal at 'another site' modifies the activity/function of a protein. In fact, with the recognition of the generality of the structural disorder of proteins and the landscape theory of protein structure, a 'new view' of allostery started to emerge, in which emphasis is placed on ligand-induced shifts in the conformational ensemble of the protein. The ensuing changes in ligand binding/catalytic activity might stem from coupled folding transitions of distinct binding sites or remodeling of the conformational landscape to entropically favor a particular downstream binding/catalytic event. The ensuing sigmoidal binding isotherm cannot be described by a simple saturation; rather, it shows signs of cooperation between ligands. If binding of one ligand weakens that of the others, one can also speak about negative cooperativity. To elucidate the underlying mechanistic changes, two models have been suggested, which, even today, form the basis of our textbook wisdom of this phenomenon