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 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 Extreme Fuzziness: Direct Interactions between Two IDPs

Biomolecules ◽  
2019 ◽  
Vol 9 (3) ◽  
pp. 81 ◽  
Author(s):  
Wenning Wang ◽  
Dongdong Wang
Keyword(s):  
Single Molecule ◽  
Protein Interaction ◽  
Protein Interactions ◽  
Intrinsically Disordered Proteins ◽  
Conformational Dynamics ◽  
Resonance Energy ◽  
Disordered Proteins ◽  
Full Spectrum ◽  
Intrinsically Disordered ◽  
Binding Mechanisms

Protein interactions involving intrinsically disordered proteins (IDPs) greatly extend the range of binding mechanisms available to proteins. In interactions employing coupled folding and binding, IDPs undergo disorder-to-order transitions to form a complex with a well-defined structure. In many other cases, IDPs retain structural plasticity in the final complexes, which have been defined as the fuzzy complexes. While a large number of fuzzy complexes have been characterized with variety of fuzzy patterns, many of the interactions are between an IDP and a structured protein. Thus, whether two IDPs can interact directly to form a fuzzy complex without disorder-to-order transition remains an open question. Recently, two studies of interactions between IDPs (4.1G-CTD/NuMA and H1/ProTα) have found a definite answer to this question. Detailed characterizations combined with nuclear magnetic resonance (NMR), single-molecule Förster resonance energy transfer (smFRET) and molecular dynamics (MD) simulation demonstrate that direct interactions between these two pairs of IDPs do form fuzzy complexes while retaining the conformational dynamics of the isolated proteins, which we name as the extremely fuzzy complexes. Extreme fuzziness completes the full spectrum of protein-protein interaction modes, suggesting that a more generalized model beyond existing binding mechanisms is required. Previous models of protein interaction could be applicable to some aspects of the extremely fuzzy interactions, but in more general sense, the distinction between native and nonnative contacts, which was used to understand protein folding and binding, becomes obscure. Exploring the phenomenon of extreme fuzziness may shed new light on molecular recognition and drug design.

Mathematical and Computational Techniques for Drug Discovery: Promises and Developments

2019 ◽  
Vol 18 (32) ◽  
pp. 2774-2799 ◽  
Author(s):  
Krishnan Balasubramanian
Keyword(s):  
Drug Discovery ◽  
Protein Interactions ◽  
Quantum Chemical ◽  
Intrinsically Disordered Proteins ◽  
Hepatitis Virus ◽  
Disordered Proteins ◽  
Computational Techniques ◽  
Large Set ◽  
Structural Protein ◽  
Intrinsically Disordered

We review various mathematical and computational techniques for drug discovery exemplifying some recent works pertinent to group theory of nested structures of relevance to phylogeny, topological, computational and combinatorial methods for drug discovery for multiple viral infections. We have reviewed techniques from topology, combinatorics, graph theory and knot theory that facilitate topological and mathematical characterizations of protein-protein interactions, molecular-target interactions, proteomics, genomics and statistical data reduction procedures for a large set of starting chemicals in drug discovery. We have provided an overview of group theoretical techniques pertinent to phylogeny, protein dynamics especially in intrinsically disordered proteins, DNA base permutations and related algorithms. We consider computational techniques derived from high level quantum chemical computations such as QM/MM ONIOM methods, quantum chemical optimization of geometries complexes, and molecular dynamics methods for providing insights into protein-drug interactions. We have considered complexes pertinent to Hepatitis Virus C non-structural protein 5B polymerase receptor binding of C5-Arylidebne rhodanines, complexes of synthetic potential vaccine molecules with dengue virus (DENV) and HIV-1 virus as examples of various simulation studies that exemplify the utility of computational tools. It is demonstrated that these combinatorial and computational techniques in conjunction with experiments can provide promising new insights into drug discovery. These techniques also demonstrate the need to consider a new multiple site or allosteric binding approach to drug discovery, as these studies reveal the existence of multiple binding sites.

scholarly journals Disorder in a two-domain neuronal Ca2+-binding protein regulates domain stability and dynamics using ligand mimicry

2020 ◽  
Author(s):  
Lasse Staby ◽  
Katherine R. Kemplen ◽  
Amelie Stein ◽  
Michael Ploug ◽  
Jane Clarke ◽  
...  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Three Dimensional ◽  
Life Time ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Order And Disorder ◽  
C Terminus ◽  
Close Relationship ◽  
Stability Dynamics ◽  
And Function

Abstract Understanding the interplay between sequence, structure and function of proteins has been complicated in recent years by the discovery of intrinsically disordered proteins (IDPs), which perform biological functions in the absence of a well-defined three-dimensional fold. Disordered protein sequences account for roughly 30% of the human proteome and in many proteins, disordered and ordered domains coexist. However, few studies have assessed how either feature affects the properties of the other. In this study, we examine the role of a disordered tail in the overall properties of the two-domain, calcium-sensing protein neuronal calcium sensor 1 (NCS-1). We show that loss of just six of the 190 residues at the flexible C-terminus is sufficient to severely affect stability, dynamics, and folding behavior of both ordered domains. We identify specific hydrophobic contacts mediated by the disordered tail that may be responsible for stabilizing the distal N-terminal domain. Moreover, sequence analyses indicate the presence of an LSL-motif in the tail that acts as a mimic of native ligands critical to the observed order–disorder communication. Removing the disordered tail leads to a shorter life-time of the ligand-bound complex likely originating from the observed destabilization. This close relationship between order and disorder may have important implications for how investigations into mixed systems are designed and opens up a novel avenue of drug targeting exploiting this type of behavior.

scholarly journals Enhancing Binding Affinity of an Intrinsically Disordered Protein by α-Methylation of Key Amino Acid Residues

2019 ◽  
Author(s):  
Valentin Bauer ◽  
Boris Schmidtgall ◽  
Gergő Gógl ◽  
Jozica Dolenc ◽  
Judit Osz ◽  
...  
Keyword(s):  
Amino Acids ◽  
Protein Interactions ◽  
Intrinsically Disordered Proteins ◽  
Intrinsically Disordered Protein ◽  
Selective Inhibition ◽  
Disordered Proteins ◽  
Creb Binding Protein ◽  
Alpha Helices ◽  
Intrinsically Disordered ◽  
Order Of Magnitude

Intrinsically disordered proteins (IDPs), which undergo folding upon binding to their targets, are critical players in protein interaction networks. Here we demonstrate that incorporation of non-canonical alpha-methylated amino acids into the unstructured activation domain of the transcriptional coactivator ACTR can stabilize helical conformations and strengthen binding interactions with the nuclear coactivator binding domain (NCBD) of CREB-binding protein (CBP). A combinatorial alpha-methylation scan of the ACTR sequence converged on two substitutions at positions 1055 and 1076 that increase affinity for both NCBD and the full length 270 kDa CBP by one order of magnitude. The first X-ray structure of the modified ACTR domain bound to NCBD revealed that the key alpha-methylated amino acids were localized within alpha-helices. Biophysical studies showed that the observed changes in binding energy are the result of long-range interactions and redistribution of enthalpy and entropy. This proof-of-concept study establishes a potential strategy for selective inhibition of protein-protein interactions involving IDPs in cells.<br>

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

Structural characterization of intrinsically disordered proteins by the combined use of NMR and SAXS

2012 ◽  
Vol 40 (5) ◽  
pp. 955-962 ◽  
Author(s):  
Nathalie Sibille ◽  
Pau Bernadó
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Dynamic Models ◽  
Dimensional Space ◽  
Three Dimensional ◽  
Main Tool ◽  
Structural Features ◽  
Disordered Proteins ◽  
Dimensional Structure ◽  
Intrinsically Disordered ◽  
Conformational Preferences

In recent years, IDPs (intrinsically disordered proteins) have emerged as pivotal actors in biology. Despite IDPs being present in all kingdoms of life, they are more abundant in eukaryotes where they are involved in the vast majority of regulation and signalling processes. The realization that, in some cases, functional states of proteins were partly or fully disordered was in contradiction to the traditional view where a well defined three-dimensional structure was required for activity. Several experimental evidences indicate, however, that structural features in IDPs such as transient secondary-structural elements and overall dimensions are crucial to their function. NMR has been the main tool to study IDP structure by probing conformational preferences at residue level. Additionally, SAXS (small-angle X-ray scattering) has the capacity to report on the three-dimensional space sampled by disordered states and therefore complements the local information provided by NMR. The present review describes how the synergy between NMR and SAXS can be exploited to obtain more detailed structural and dynamic models of IDPs in solution. These combined strategies, embedded into computational approaches, promise the elucidation of the structure–function properties of this important, but elusive, family of biomolecules.

scholarly journals Transient Secondary Structures as General Target-Binding Motifs in Intrinsically Disordered Proteins

2018 ◽  
Vol 19 (11) ◽  
pp. 3614 ◽  
Author(s):  
Do-Hyoung Kim ◽  
Kyou-Hoon Han
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Three Dimensional ◽  
Secondary Structures ◽  
Disordered Proteins ◽  
Ample Evidence ◽  
Binding Motifs ◽  
Intrinsically Disordered ◽  
Long Time ◽  
Science Community ◽  
Target Binding

Intrinsically disordered proteins (IDPs) are unorthodox proteins that do not form three-dimensional structures under non-denaturing conditions, but perform important biological functions. In addition, IDPs are associated with many critical diseases including cancers, neurodegenerative diseases, and viral diseases. Due to the generic name of “unstructured” proteins used for IDPs in the early days, the notion that IDPs would be completely unstructured down to the level of secondary structures has prevailed for a long time. During the last two decades, ample evidence has been accumulated showing that IDPs in their target-free state are pre-populated with transient secondary structures critical for target binding. Nevertheless, such a message did not seem to have reached with sufficient clarity to the IDP or protein science community largely because similar but different expressions were used to denote the fundamentally same phenomenon of presence of such transient secondary structures, which is not surprising for a quickly evolving field. Here, we summarize the critical roles that these transient secondary structures play for diverse functions of IDPs by describing how various expressions referring to transient secondary structures have been used in different contexts.

scholarly journals Chasing coevolutionary signals in intrinsically disordered proteins complexes

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Javier A. Iserte ◽  
Tamas Lazar ◽  
Silvio C. E. Tosatto ◽  
Peter Tompa ◽  
Cristina Marino-Buslje
Keyword(s):  
Protein Interactions ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Protein Protein Interactions ◽  
Contact Prediction ◽  
Intrinsically Disordered ◽  
Regulatory Processes ◽  
Wide Range ◽  
Predict Protein Structure ◽  
Biological Interpretation

Abstract Intrinsically disordered proteins/regions (IDPs/IDRs) are crucial components of the cell, they are highly abundant and participate ubiquitously in a wide range of biological functions, such as regulatory processes and cell signaling. Many of their important functions rely on protein interactions, by which they trigger or modulate different pathways. Sequence covariation, a powerful tool for protein contact prediction, has been applied successfully to predict protein structure and to identify protein–protein interactions mostly of globular proteins. IDPs/IDRs also mediate a plethora of protein–protein interactions, highlighting the importance of addressing sequence covariation-based inter-protein contact prediction of this class of proteins. Despite their importance, a systematic approach to analyze the covariation phenomena of intrinsically disordered proteins and their complexes is still missing. Here we carry out a comprehensive critical assessment of coevolution-based contact prediction in IDP/IDR complexes and detail the challenges and possible limitations that emerge from their analysis. We found that the coevolutionary signal is faint in most of the complexes of disordered proteins but positively correlates with the interface size and binding affinity between partners. In addition, we discuss the state-of-art methodology by biological interpretation of the results, formulate evaluation guidelines and suggest future directions of development to the field.

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