Beáta Szabó

DisProt: The database of disordered proteins

The Database of Protein Disorder (DisProt) links structure and function information for intrinsically disordered proteins (IDPs). Intrinsically disordered proteins do not form a fixed three-dimensional structure under physiological conditions, either in their entireties or in segments or regions. We define IDP as a protein that contains at least one experimentally determined disordered region. Although lacking fixed structure, IDPs and regions carry out important biological functions, being typically involved in regulation, signaling and control. Such functions can involve high-specificity low-affinity interactions, the multiple binding of one protein to many partners and the multiple binding of many proteins to one partner. These three features are all enabled and enhanced by protein intrinsic disorder. One of the major hindrances in the study of IDPs has been the lack of organized information. DisProt was developed to enable IDP research by collecting and organizing knowledge regarding the experimental characterization and the functional associations of IDPs. In addition to being a unique source of biological information, DisProt opens doors for a plethora of bioinformatics studies. DisProt is openly available at .

Intrinsically disordered proteins undergo and assist folding transitions in the proteome.

The common notion in the protein world holds that proteins are synthesized as a linear polypeptide chain, followed by folding into a unique, functional 3D-structure. As outlined in many articles of this volume, this is in fact the case for a great proportion of the proteome. Many proteins and protein domains, however, are intrinsically disordered (IDPs), i.e., they cannot fold on their own, but often undergo a folding transition in the presence of a binding partner. This binding-induced folding process shows strong conceptual parallels with the folding of globular proteins, in a sense that it can proceed via two routes, either induction of the folded conformation from an initial random state or selection of a pre-formed state already present in the ensemble. In addition, we show that IDPs not only undergo folding themselves, they also assist the folding process of other proteins as chaperones, and even contribute to the quality control processes of the cell, in which irreparably misfolded proteins are recognized and tagged for proteasomal degradation. These various mechanisms suggest that structural disorder, in a biological context, is linked with protein folding in several ways, in which both the IDP and its partner may undergo reciprocal structural transitions.

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.

Structural disorder and local order of hNopp140.

Human nucleolar phosphoprotein p140 (hNopp 140) is a highly phosphorylated protein inhibitor of casein kinase 2 (CK2). As in the case of many kinase-inhibitor systems, the inhibitor has been described to belong to the family of intrinsically disordered proteins (IDPs), which often utilize transient structural elements to bind their cognate enzyme. Here we investigated the structural status of this protein both to provide distinct lines of evidence for its disorder and to point out its transient structure potentially involved in interactions and also its tendency to aggregate. Structural disorder of hNopp140 is apparent by its anomalous electrophoretic mobility, protease sensitivity, heat stability, hydrodynamic behavior on size-exclusion chromatography, (1)H NMR spectrum and differential scanning calorimetry scan. hNopp140 has a significant tendency to aggregate and the change of its circular dichroism spectrum in the presence of 0-80% TFE suggests a tendency to form local helical structures. Wide-line NMR measurements suggest the overall disordered character of the protein. In all, our data suggest that this protein falls into the pre-molten globule state of IDPs, with a significant tendency to become ordered in the presence of its partner as demonstrated in the presence of transcription factor IIB (TFIIB).

Complex formation of EphB1/Nck/Caskin1 leads to tyrosine phosphorylation and structural changes of the Caskin1 SH3 domain

BackgroundScaffold proteins have an important role in the regulation of signal propagation. These proteins do not possess any enzymatic activity but can contribute to the formation of multiprotein complexes. Although scaffold proteins are present in all cell types, the nervous system contains them in the largest amount. Caskin proteins are typically present in neuronal cells, particularly, in the synapses. However, the signaling mechanisms by which Caskin proteins are regulated are largely unknown.ResultsHere we demonstrate that EphB1 receptor tyrosine kinase can recruit Caskin1 through the adaptor protein Nck. Upon activation of the receptor kinase, the SH2 domain of Nck binds to one of its tyrosine residues, while Nck SH3 domains interact with the proline-rich domain of Caskin1. Complex formation of the receptor, adaptor and scaffold proteins results in the tyrosine phosphorylation of Caskin1 on its SH3 domain. The phosphorylation sites were identified by mass-spectrometry as tyrosines 296 and 336. To reveal the structural consequence of this phosphorylation, CD spectroscopy was performed. This measurement suggests that upon tyrosine phosphorylation the structure of the Caskin1 SH3 domain changes significantly.ConclusionTaken together, we propose that the scaffold protein Caskin1 can form a complex with the EphB1 tyrosine kinase via the Nck protein as a linker. Complex formation results in tyrosine phosphorylation of the Caskin1 SH3 domain. Although we were not able to identify any physiological partner of the SH3 domain so far, we could demonstrate that phosphorylation on conserved tyrosine residues results in marked changes in the structure of the SH3 domain.

Computational Models of Auditory Scene Analysis: A Review

Auditory scene analysis (ASA) refers to the process (es) of parsing the complex acoustic input into auditory perceptual objects representing either physical sources or temporal sound patterns, such as melodies, which contributed to the sound waves reaching the ears. A number of new computational models accounting for some of the perceptual phenomena of ASA have been published recently. Here we provide a theoretically motivated review of these computational models, aiming to relate their guiding principles to the central issues of the theoretical framework of ASA. Specifically, we ask how they achieve the grouping and separation of sound elements and whether they implement some form of competition between alternative interpretations of the sound input. We consider the extent to which they include predictive processes, as important current theories suggest that perception is inherently predictive, and also how they have been evaluated. We conclude that current computational models of ASA are fragmentary in the sense that rather than providing general competing interpretations of ASA, they focus on assessing the utility of specific processes (or algorithms) for finding the causes of the complex acoustic signal. This leaves open the possibility for integrating complementary aspects of the models into a more comprehensive theory of ASA.

Intrinsic protein disorder in histone lysine methylation

AbstractHistone lysine methyltransferases (HKMTs), catalyze mono-, di- and trimethylation of lysine residues, resulting in a regulatory pattern that controls gene expression. Their involvement in many different cellular processes and diseases makes HKMTs an intensively studied protein group, but scientific interest so far has been concentrated mostly on their catalytic domains. In this work we set out to analyze the structural heterogeneity of human HKMTs and found that many contain long intrinsically disordered regions (IDRs) that are conserved through vertebrate species. Our predictions show that these IDRs contain several linear motifs and conserved putative binding sites that harbor cancer-related SNPs. Although there are only limited data available in the literature, some of the predicted binding regions overlap with interacting segments identified experimentally. The importance of a disordered binding site is illustrated through the example of the ternary complex between MLL1, menin and LEDGF/p75. Our suggestion is that intrinsic protein disorder plays an as yet unrecognized role in epigenetic regulation, which needs to be further elucidated through structural and functional studies aimed specifically at the disordered regions of HKMTs. Reviewers: This article was reviewed by Arne Elofsson and Piotr Zielenkiewicz.

Multiple fuzzy interactions in the moonlighting function of thymosin-β4

Thymosine β4 (Tß4) is a 43 amino acid long intrinsically disordered protein (IDP), which was initially identified as an actin-binding and sequestering molecule. Later it was described to have multiple other functions, such as regulation of endothelial cell differentiation, blood vessel formation, wound repair, cardiac cell migration, and survival.1 The various functions of Tβ4 are mediated by interactions with distinct and structurally unrelated partners, such as PINCH, ILK, and stabilin-2, besides the originally identified G-actin. Although the cellular readout of these interactions and the formation of these complexes have been thoroughly described, no attempt was made to study these interactions in detail, and to elucidate the thermodynamic, kinetic, and structural underpinning of this range of moonlighting functions. Because Tβ4 is mostly disordered, and its 4 described partners are structurally unrelated (the CTD of stabilin-2 is actually fully disordered), it occurred to us that this system might be ideal to characterize the structural adaptability and ensuing moonlighting functions of IDPs. Unexpectedly, we found that Tβ4 engages in multiple weak, transient, and fuzzy interactions, i.e., it is capable of mediating distinct yet specific interactions without adapting stable folded structures.

Structuring forces and β-diversity of benthic diatom metacommunities in soda pans of the Carpathian Basin

ABSTRACT Small soda lakes represent one of the most vulnerable ecosystem types due to their high hydrological sensitivity to climate change and anthropogenic interventions. Since diatoms are excellent bioindicators, determining the β-diversity and the structuring dynamics of diatom metacommunities can provide valuable information for conservation planning for soda pans. In this study, two diatom metacommunities were surveyed monthly during a one-year period from distinct regions of the Carpathian basin: the Fertő-Hanság National Park (FH) between 2013 and 2014, and the Danube-Tisza Interfluve (DT) between 2014 and 2015. We explored whether β-diversity of diatom assemblages in the two regions is enhanced by species turnover or nestedness (related to richness differences) and investigated the role of deterministic and stochastic processes in shaping β-diversity patterns. Furthermore, we evaluated the contribution of environmental variables, geographic distance and temporal variation to community structure. High β-diversity (>90%) was revealed for both metacommunities, and was maintained primarily by species turnover. Within the metacommunity of the DT where the natural hydrological cycle of soda pans is not disturbed, diatom communities assembled mainly due to the selection force of environment at a spatiotemporal scale. In the soda pans located in the habitat reconstruction area of the FH, besides species-sorting, significant temporal variation in community structure appeared as a result of water management and periodic water supply. Our results point to the need for a conservation management strategy which maintains the natural hydrological regime of small saline lakes, and therefore their habitat heterogeneity which is of high conservation value.

Benthic diatom metacommunity across small freshwater lakes: driving mechanisms, β-diversity and ecological uniqueness

In this study, driving forces and diversity patterns of a benthic diatom metacommunity across small freshwater lakes exhibiting environmental heterogeneity were investigated. Furthermore, local (LCBD) and species (SCBD) contributions to β-diversity and their driving parameters were assessed with abundance- and incidence-based analyses. Our results revealed that both spatial distance and environmental heterogeneity affected the community assembly, which corresponds most to the mass-effect (ME) concept. This theory was confirmed by high α-diversity of sampling sites; however, high overall β-diversity enhanced mainly by turnover contradicted the ME paradigm. LCBD indices were affected by environmental variables; furthermore, LCBD and LCBD in terms of species replacement showed a strong positive correlation. The ecologically most unique sites hosted relatively low species richness, and common species with intermediate-sized or broad niches contributed mostly to the regional β-diversity. However, abundance- and incidence-based calculations revealed different relationships of SCBD with the species’ total abundance and the number of occupied sites. Consequently, we favor the previous suggestions that comprehensive research focusing on conservation should incorporate the investigation of LCBD, SCBD, species-rich sites and also ecologically restricted species. Moreover, in assessing ecological uniqueness, both abundance and binary data sets should be considered since they might shed light on distinct patterns.