scholarly journals αα-hub domains and intrinsically disordered proteins – a decisive combo

2020 ◽  
pp. jbc.REV120.012928
Author(s):  
Katrine Bugge ◽  
Lasse Staby ◽  
Edoardo Salladini ◽  
Rasmus G. Falbe-Hansen ◽  
Birthe B. Kragelund ◽  
...  
Keyword(s):  
Protein Interaction ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Protein Protein Interaction ◽  
Intrinsically Disordered ◽  
New Concepts ◽  
Protein Protein Interaction Networks ◽  
Living Organisms ◽  
The Individual ◽  
New Research

Hub proteins are central nodes in protein–protein interaction networks with critical importance to all living organisms. Recently, a new group of folded hub domains, the αα-hubs, was defined based on a shared αα-hairpin super-secondary structural foundation. The members PAH, RST, TAFH, NCBD and HHD are found in large proteins such as Sin3, RCD1, TAF4, CBP and harmonin, which organize disordered transcriptional regulators and membrane scaffolds in interactomes of importance to human diseases and plant quality. In this review, studies of structures, functions, and complexes across the αα-hubs are described and compared to provide a unified description of the group. This analysis expands the associated molecular concepts of “one domain – one superbinding site”, motif-based ligand binding, and coupled folding and binding of intrinsically disordered ligands to additional concepts of importance to signal fidelity. These include context, motif reversibility, multivalency, complex heterogeneity, synergistic αα-hub:ligand folding, accessory binding-sites, and supramodules. We propose that these multifaceted protein–protein interaction properties are made possible by the characteristics of the αα-hub fold, including super-site properties, dynamics, variable topologies, accessory helices and malleability and abetted by adaptability of the disordered ligands. Critically, these features provide additional filters for specificity. With the presentations of new concepts, this review opens for new research questions addressing properties across the group, which are driven from concepts discovered in studies of the individual members. Combined, the members of the αα-hubs are ideal models for deconvoluting signal fidelity maintained by folded hubs and their interactions with intrinsically disordered ligands.

scholarly journals IDPpi: Protein-Protein Interaction Analyses of Human Intrinsically Disordered Proteins

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Vladimir Perovic ◽  
Neven Sumonja ◽  
Lindsey A. Marsh ◽  
Sandro Radovanovic ◽  
Milan Vukicevic ◽  
...  
Keyword(s):  
Protein Interaction ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Protein Protein Interaction ◽  
Intrinsically Disordered

scholarly journals Functional Segments on Intrinsically Disordered Regions in Disease-Related Proteins

Biomolecules ◽  
2019 ◽  
Vol 9 (3) ◽  
pp. 88 ◽  
Author(s):  
Hiroto Anbo ◽  
Masaya Sato ◽  
Atsushi Okoshi ◽  
Satoshi Fukuchi
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Protein Protein Interaction ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Protein Protein Interaction Networks ◽  
Digestive System Diseases ◽  
To Come ◽  
Related Proteins ◽  
Disordered Regions

One of the unique characteristics of intrinsically disordered proteins (IPDs) is the existence of functional segments in intrinsically disordered regions (IDRs). A typical function of these segments is binding to partner molecules, such as proteins and DNAs. These segments play important roles in signaling pathways and transcriptional regulation. We conducted bioinformatics analysis to search these functional segments based on IDR predictions and database annotations. We found more than a thousand potential functional IDR segments in disease-related proteins. Large fractions of proteins related to cancers, congenital disorders, digestive system diseases, and reproductive system diseases have these functional IDRs. Some proteins in nervous system diseases have long functional segments in IDRs. The detailed analysis of some of these regions showed that the functional segments are located on experimentally verified IDRs. The proteins with functional IDR segments generally tend to come and go between the cytoplasm and the nucleus. Proteins involved in multiple diseases tend to have more protein-protein interactors, suggesting that hub proteins in the protein-protein interaction networks can have multiple impacts on human diseases.

scholarly journals Connecting the αα-hubs: same fold, disordered ligands, new functions

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Lasse Staby ◽  
Katrine Bugge ◽  
Rasmus Greve Falbe-Hansen ◽  
Edoardo Salladini ◽  
Karen Skriver ◽  
...  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Telomere Elongation ◽  
Protein Protein Interaction ◽  
Intrinsically Disordered ◽  
Functional Understanding ◽  
Signal Specificity ◽  
Telomere Regulation ◽  
Secondary Structure Motif

Abstract Background Signal fidelity depends on protein–protein interaction–‘hubs’ integrating cues from large interactomes. Recently, and based on a common secondary structure motif, the αα-hubs were defined, which are small α-helical domains of large, modular proteins binding intrinsically disordered transcriptional regulators. Methods Comparative structural biology. Results We assign the harmonin-homology-domain (HHD, also named the harmonin N-terminal domain, NTD) present in large proteins such as harmonin, whirlin, cerebral cavernous malformation 2, and regulator of telomere elongation 1 to the αα-hubs. The new member of the αα-hubs expands functionality to include scaffolding of supra-modular complexes mediating sensory perception, neurovascular integrity and telomere regulation, and reveal novel features of the αα-hubs. As a common trait, the αα-hubs bind intrinsically disordered ligands of similar properties integrating similar cellular cues, but without cross-talk. Conclusion The inclusion of the HHD in the αα-hubs has uncovered new features, exemplifying the utility of identifying groups of hub domains, whereby discoveries in one member may cross-fertilize discoveries in others. These features make the αα-hubs unique models for decomposing signal specificity and fidelity. Using these as models, together with other suitable hub domain, we may advance the functional understanding of hub proteins and their role in cellular communication and signaling, as well as the role of intrinsically disordered proteins in signaling networks.

scholarly journals A comprehensive motifs-based interactome of the C/EBPα transcription factor

2020 ◽  
Author(s):  
Evelyn Ramberger ◽  
Valeria Sapozhnikova ◽  
Elisabeth Kowenz-Leutz ◽  
Karin Zimmermann ◽  
Nathalie Nicot ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Protein Interaction ◽  
Intrinsically Disordered Proteins ◽  
Arginine Methylation ◽  
Disordered Proteins ◽  
List Type ◽  
Short Linear Motifs ◽  
Intrinsically Disordered ◽  
Linear Motifs ◽  
Factor C

AbstractThe pioneering transcription factor C/EBPα coordinates cell fate and cell differentiation. C/EBPα represents an intrinsically disordered protein with multiple short linear motifs and extensive post-translational side chain modifications (PTM), reflecting its modularity and functional plasticity. Here, we combined arrayed peptide matrix screening (PRISMA) with biotin ligase proximity labeling proteomics (BioID) to generate a linear, isoform specific and PTM-dependent protein interaction map of C/EBPα in myeloid cells. The C/EBPα interactome comprises promiscuous and PTM-regulated interactions with protein machineries involved in gene expression, epigenetics, genome organization, DNA replication, RNA processing, and nuclear transport as the basis of functional C/EBPα plasticity. Protein interaction hotspots were identified that coincide with homologous conserved regions of the C/EBP family and revealed interaction motifs that score as molecular recognition features (MoRF). PTMs alter the interaction spectrum of multi-valent C/EBP-motifs to configure a multimodal transcription factor hub that allows interaction with multiple co-regulatory components, including BAF/SWI-SNF or Mediator complexes. Combining PRISMA and BioID acts as a powerful strategy to systematically explore the interactomes of intrinsically disordered proteins and their PTM-regulated, multimodal capacity.Key pointsIntegration of proximity labeling and arrayed peptide screen proteomics refines the interactome of C/EBPα isoformsHotspots of protein interactions in C/EBPα mostly occur in conserved short linear motifsInteractions of the BAF/SWI-SNF complex with C/EBPα are modulated by arginine methylation and isoform statusThe integrated experimental strategy suits systematic interactome studies of intrinsically disordered proteins

scholarly journals Advanced Graph Traversal used in Protein Interactions Network and Systems Biology

2018 ◽  
Author(s):  
Rashmi Rameshwari ◽  
Shilpa S Chapadgaonkar ◽  
T. V. Prasad
Keyword(s):  
Systems Biology ◽  
Protein Interaction ◽  
Protein Interactions ◽  
Intrinsically Disordered Proteins ◽  
Three Dimensional ◽  
Holistic Approach ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Graph Traversal ◽  
Interactions Network

AbstractA methodological framework of graph traversal in Systems Biology is presented here. At present there is need to investigate system rather individual component. The proposed analysis generalizes the various idea of network representations of protein interactions. This approach highlights various methods used in construction of protein interaction graph or network using suitable algorithm. The network nodes represent protein residues. Two nodes are connected if two residues are functionally correlated during the protein interaction event. The analysis of the resulting network enables the importance of each protein for its interactions. Furthermore, the determination of the pattern of edge between residues yields insights into the function prediction of an interaction. This is of special interest to investigate intrinsically disordered proteins, since it is difficult to determine structural (three-dimensional) architecture of each proteins in protein interactions network. In present work various approaches for protein interactions network construction, models and methods along with graph theories has been discussed which can be used to reveal hidden properties and features of a network. Further effective algorithm for visualization of protein interactions is suggested. As construction of Biological network is dependent on various properties of graph. A holistic approach such as Systems Biology approach can better solve the problem. This network profiling combined with knowledge extraction will help biologist to explore hidden information in genome as well as in proteome..

scholarly journals The disordered boundary of the cell: emerging properties of membrane-bound intrinsically disordered proteins

2019 ◽  
Vol 10 (1) ◽  
pp. 25-36 ◽  
Author(s):  
Irrem-Laareb Mohammad ◽  
Borja Mateos ◽  
Miquel Pons
Keyword(s):  
Lipid Bilayers ◽  
Protein Interactions ◽  
Intrinsically Disordered Proteins ◽  
Intrinsically Disordered Protein ◽  
Disordered Proteins ◽  
Protein Protein Interactions ◽  
Intrinsically Disordered ◽  
High Concentrations ◽  
The Individual ◽  
Confined Environment

AbstractWe define the disordered boundary of the cell (DBC) as the system formed by membrane tethered intrinsically disordered protein regions, dynamically coupled to the underlying membrane.The emerging properties of the DBC makes it a global system of study, which cannot be understood from the individual properties of their components. Similarly, the properties of lipid bilayers cannot be understood from just the sum of the properties of individual lipid molecules.The highly anisotropic confined environment, restricting the position and orientation of interacting sites, is affecting the properties of individual disordered proteins. In fact, the collective effect caused by high concentrations of disordered proteins extend beyond the sum of individual effects.Examples of emerging properties of the DBC include enhanced protein-protein interactions, protein-driven phase separations, Z-compartmentalization, and protein modulated electrostatics.

scholarly journals Structure and dynamics conspire in the evolution of affinity between intrinsically disordered proteins

2018 ◽  
Vol 4 (10) ◽  
pp. eaau4130 ◽  
Author(s):  
Per Jemth ◽  
Elin Karlsson ◽  
Beat Vögeli ◽  
Brenda Guzovsky ◽  
Eva Andersson ◽  
...  
Keyword(s):  
Protein Interaction ◽  
Protein Interactions ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Solvent Accessible Surface Area ◽  
Resonance Spectroscopy ◽  
Protein Protein Interactions ◽  
Structural Dynamic ◽  
Intrinsically Disordered ◽  
Structure And Dynamics

In every established species, protein-protein interactions have evolved such that they are fit for purpose. However, the molecular details of the evolution of new protein-protein interactions are poorly understood. We have used nuclear magnetic resonance spectroscopy to investigate the changes in structure and dynamics during the evolution of a protein-protein interaction involving the intrinsically disordered CREBBP (CREB-binding protein) interaction domain (CID) and nuclear coactivator binding domain (NCBD) from the transcriptional coregulators NCOA (nuclear receptor coactivator) and CREBBP/p300, respectively. The most ancient low-affinity “Cambrian-like” [540 to 600 million years (Ma) ago] CID/NCBD complex contained less secondary structure and was more dynamic than the complexes from an evolutionarily younger “Ordovician-Silurian” fish ancestor (ca. 440 Ma ago) and extant human. The most ancient Cambrian-like CID/NCBD complex lacked one helix and several interdomain interactions, resulting in a larger solvent-accessible surface area. Furthermore, the most ancient complex had a high degree of millisecond-to-microsecond dynamics distributed along the entire sequences of both CID and NCBD. These motions were reduced in the Ordovician-Silurian CID/NCBD complex and further redistributed in the extant human CID/NCBD complex. Isothermal calorimetry experiments show that complex formation is enthalpically favorable and that affinity is modulated by a largely unfavorable entropic contribution to binding. Our data demonstrate how changes in structure and motion conspire to shape affinity during the evolution of a protein-protein complex and provide direct evidence for the role of structural, dynamic, and frustrational plasticity in the evolution of interactions between intrinsically disordered proteins.

scholarly journals Effective concentrations enforced by intrinsically disordered linkers are governed by polymer physics

2019 ◽  
Vol 116 (46) ◽  
pp. 23124-23131 ◽  
Author(s):  
Charlotte S. Sørensen ◽  
Magnus Kjaergaard
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Polymer Physics ◽  
Disordered Proteins ◽  
Multidomain Proteins ◽  
Fluorescent Biosensor ◽  
Intrinsically Disordered ◽  
Theoretical Predictions ◽  
Quantitative Understanding ◽  
The Individual ◽  
The Relationship

Many multidomain proteins contain disordered linkers that regulate interdomain contacts, and thus the effective concentrations that govern intramolecular reactions. Effective concentrations are rarely measured experimentally, and therefore little is known about how they relate to linker architecture. We have directly measured the effective concentrations enforced by disordered protein linkers using a fluorescent biosensor. We show that effective concentrations follow simple geometric models based on polymer physics, offering an indirect method to probe the structural properties of the linker. The compaction of the disordered linker depends not only on net charge, but also on the type of charged residues. In contrast to theoretical predictions, we found that polyampholyte linkers can contract to similar dimensions as globular proteins. Hydrophobicity has little effect in itself, but aromatic residues lead to strong compaction, likely through π-interactions. Finally, we find that the individual contributors to chain compaction are not additive. We thus demonstrate that direct measurement of effective concentrations can be used in systematic studies of the relationship between sequence and structure of intrinsically disordered proteins. A quantitative understanding of the relationship between effective concentration and linker sequence will be crucial for understanding disorder-based allosteric regulation in multidomain proteins.

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