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 Evolution of A bHLH Interaction Motif

2021 ◽  
Vol 22 (1) ◽  
pp. 447
Author(s):  
Peter S. Millard ◽  
Birthe B. Kragelund ◽  
Meike Burow
Keyword(s):  
Arabidopsis Thaliana ◽  
Transcription Factor ◽  
Intrinsically Disordered Proteins ◽  
Sequence Similarity ◽  
Disordered Proteins ◽  
Transcription Factor Family ◽  
Defense Compounds ◽  
Short Linear Motifs ◽  
Intrinsically Disordered ◽  
Linear Motifs

Intrinsically disordered proteins and regions with their associated short linear motifs play key roles in transcriptional regulation. The disordered MYC-interaction motif (MIM) mediates interactions between MYC and MYB transcription factors in Arabidopsis thaliana that are critical for constitutive and induced glucosinolate (GLS) biosynthesis. GLSs comprise a class of plant defense compounds that evolved in the ancestor of the Brassicales order. We used a diverse set of search strategies to discover additional occurrences of the MIM in other proteins and in other organisms and evaluate the findings by means of structural predictions, interaction assays, and biophysical experiments. Our search revealed numerous MIM instances spread throughout the angiosperm lineage. Experiments verify that several of the newly discovered MIM-containing proteins interact with MYC TFs. Only hits found within the same transcription factor family and having similar characteristics could be validated, indicating that structural predictions and sequence similarity are good indicators of whether the presence of a MIM mediates interaction. The experimentally validated MIMs are found in organisms outside the Brassicales order, showing that MIM function is broader than regulating GLS biosynthesis.

scholarly journals Proteome-wide analysis of human disease mutations in short linear motifs: neglected players in cancer?

2014 ◽  
Vol 10 (10) ◽  
pp. 2626-2642 ◽  
Author(s):  
Bora Uyar ◽  
Robert J. Weatheritt ◽  
Holger Dinkel ◽  
Norman E. Davey ◽  
Toby J. Gibson
Keyword(s):  
Human Disease ◽  
Intrinsically Disordered Proteins ◽  
Cellular Signaling ◽  
Human Diseases ◽  
Disordered Proteins ◽  
Short Linear Motifs ◽  
Signaling Regulation ◽  
Intrinsically Disordered ◽  
Disease Mutations ◽  
Linear Motifs

Mutations in short linear motifs impair the functions of intrinsically disordered proteins in cellular signaling/regulation and contribute substantially to human diseases.

scholarly journals Conformational propensities of intrinsically disordered proteins influence the mechanism of binding and folding

2015 ◽  
Vol 112 (31) ◽  
pp. 9614-9619 ◽  
Author(s):  
Munehito Arai ◽  
Kenji Sugase ◽  
H. Jane Dyson ◽  
Peter E. Wright
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Terminal Region ◽  
Relaxation Dispersion ◽  
Disordered Proteins ◽  
Conformational Ensemble ◽  
Induced Fit ◽  
Conformational Selection ◽  
Intrinsically Disordered ◽  
Factor C ◽  
Binding Mechanisms

Intrinsically disordered proteins (IDPs) frequently function in protein interaction networks that regulate crucial cellular signaling pathways. Many IDPs undergo transitions from disordered conformational ensembles to folded structures upon binding to their cellular targets. Several possible binding mechanisms for coupled folding and binding have been identified: folding of the IDP after association with the target (“induced fit”), or binding of a prefolded state in the conformational ensemble of the IDP to the target protein (“conformational selection”), or some combination of these two extremes. The interaction of the intrinsically disordered phosphorylated kinase-inducible domain (pKID) of the cAMP-response element binding (CREB) protein with the KIX domain of a general transcriptional coactivator CREB-binding protein (CBP) provides an example of the induced-fit mechanism. Here we show by NMR relaxation dispersion experiments that a different intrinsically disordered ligand, the transactivation domain of the transcription factor c-Myb, interacts with KIX at the same site as pKID but via a different binding mechanism that involves elements of conformational selection and induced fit. In contrast to pKID, the c-Myb activation domain has a strong propensity for spontaneous helix formation in its N-terminal region, which binds to KIX in a predominantly folded conformation. The C-terminal region of c-Myb exhibits a much smaller helical propensity and likely folds via an induced-fit process after binding to KIX. We propose that the intrinsic secondary structure propensities of pKID and c-Myb determine their binding mechanisms, consistent with their functions as inducible and constitutive transcriptional activators.

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 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 The structure of SDS22 provides insights into the mechanism of heterodimer formation with PP1

2018 ◽  
Vol 74 (12) ◽  
pp. 817-824 ◽  
Author(s):  
Meng S. Choy ◽  
Nicolas Bolik-Coulon ◽  
Tara L. Archuleta ◽  
Wolfgang Peti ◽  
Rebecca Page
Keyword(s):  
Protein Phosphatase ◽  
Intrinsically Disordered Proteins ◽  
Regulatory Proteins ◽  
Protein Phosphatase 1 ◽  
Disordered Proteins ◽  
Biological Targets ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Linear Motifs ◽  
Lrr Protein

Protein phosphatase 1 (PP1) dephosphorylates hundreds of key biological targets by associating with nearly 200 regulatory proteins to form highly specific holoenzymes. The vast majority of regulators are intrinsically disordered proteins (IDPs) and bind PP1 via short linear motifs within their intrinsically disordered regions. One of the most ancient PP1 regulators is SDS22, a protein that is conserved from yeast to mammals. Sequence analysis of SDS22 revealed that it is a leucine-rich repeat (LRR) protein, suggesting that SDS22, unlike nearly every other known PP1 regulator, is not an IDP but instead is fully structured. Here, the 2.9 Å resolution crystal structure of human SDS22 in space group P212121 is reported. SDS22 adopts an LRR fold with the horseshoe-like curvature typical for this family of proteins. The structure results in surfaces with distinct chemical characteristics that are likely to be critical for PP1 binding.

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.

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