scholarly journals Interaction of the C-Terminal Domains of Sendai Virus N and P Proteins: Comparison of Polymerase-Nucleocapsid Interactions within the Paramyxovirus Family

2007 ◽  
Vol 81 (13) ◽  
pp. 6807-6816 ◽  
Author(s):  
Klaartje Houben ◽  
Dominique Marion ◽  
Nicolas Tarbouriech ◽  
Rob W. H. Ruigrok ◽  
Laurence Blanchard
Keyword(s):  
Measles Virus ◽  
Intrinsically Disordered Proteins ◽  
Sendai Virus ◽  
Protein Complexes ◽  
Disordered Proteins ◽  
Resonance Spectroscopy ◽  
Intrinsically Disordered ◽  
Binding Interface ◽  
P Proteins ◽  
Terminal Domains

ABSTRACT Interaction of the C-terminal domains of Sendai virus (SeV) P and N proteins is crucial for RNA synthesis by correctly positioning the polymerase complex (L+P) onto the nucleocapsid (N/RNA). To better understand this mechanism within the paramyxovirus family, we have studied the complex formed by the SeV C-terminal domains of P (PX) and N (NTAIL) proteins by solution nuclear magnetic resonance spectroscopy. We have characterized SeV NTAIL, which belongs to the class of intrinsically disordered proteins, and precisely defined the binding regions within this latter domain and within PX. SeV NTAIL binds with residues 472 to 493, which have a helical propensity (residues 477 to 491) to the surface created by helices α2 and α3 of PX with a 1:1 stoichiometry, as was also found for measles virus (MV). The binding interface is dominated by charged residues, and the dissociation constant was determined to be 57 ± 18 μM under conditions of the experiment (i.e., in 0.5 M NaCl). We have also shown that the extreme C terminus of SeV NTAIL does not interact with PX, which is in contrast to MV, where a second binding site was identified. In addition, the interaction surfaces of the MV proteins are hydrophobic and a stronger binding constant was found. This gives a good illustration of how selection pressure allowed the C-terminal domains of N and P proteins to evolve concomitantly within this family of viruses in order to lead to protein complexes having the same three-dimensional fold, and thus the same function, but with completely different binding interfaces.

scholarly journals Intrinsically disordered proteins identified in the aggregate proteome serve as biomarkers of neurodegeneration

2021 ◽  
Author(s):  
Srinivas Ayyadevara ◽  
Akshatha Ganne ◽  
Meenakshisundaram Balasubramaniam ◽  
Robert J. Shmookler Reis
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Protein Complexes ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Physiological Processes ◽  
Protein Partners ◽  
And Function ◽  
Computational Analyses ◽  
Disordered Regions

AbstractA protein’s structure is determined by its amino acid sequence and post-translational modifications, and provides the basis for its physiological functions. Across all organisms, roughly a third of the proteome comprises proteins that contain highly unstructured or intrinsically disordered regions. Proteins comprising or containing extensive unstructured regions are referred to as intrinsically disordered proteins (IDPs). IDPs are believed to participate in complex physiological processes through refolding of IDP regions, dependent on their binding to a diverse array of potential protein partners. They thus play critical roles in the assembly and function of protein complexes. Recent advances in experimental and computational analyses predicted multiple interacting partners for the disordered regions of proteins, implying critical roles in signal transduction and regulation of biological processes. Numerous disordered proteins are sequestered into aggregates in neurodegenerative diseases such as Alzheimer’s disease (AD) where they are enriched even in serum, making them good candidates for serum biomarkers to enable early detection of AD.

The C-terminal domain of measles virus nucleoprotein belongs to the class of intrinsically disordered proteins that fold upon binding to their physiological partner

2004 ◽  
Vol 99 (2) ◽  
pp. 157-167 ◽  
Author(s):  
Jean-Marie Bourhis ◽  
Kenth Johansson ◽  
Véronique Receveur-Bréchot ◽  
Christopher J. Oldfield ◽  
Keith A. Dunker ◽  
...  
Keyword(s):  
Measles Virus ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Terminal Domain

scholarly journals Single-embryo phosphoproteomics reveals the importance of intrinsic disorder in cell cycle dynamics

2021 ◽  
Author(s):  
Juan Manuel Valverde ◽  
Geronimo Dubra ◽  
Henk van den Toorn ◽  
Guido van Mierlo ◽  
Michiel Vermeulen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Intrinsically Disordered Proteins ◽  
Protein Complexes ◽  
Disordered Proteins ◽  
Cell Cycles ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Egg Extracts ◽  
Cell Cycle Dynamics

Switch-like cyclin-dependent kinase (CDK)-1 activation is thought to underlie the abruptness of mitotic onset, but how CDKs can simultaneously phosphorylate many diverse substrates is unknown, and direct evidence for such phosphorylation dynamics in vivo is lacking. Here, we analysed protein phosphorylation states in single Xenopus embryos throughout synchronous cell cycles. Over a thousand phosphosites were dynamic in vivo, and assignment of cell cycle phases using egg extracts revealed hundreds of S-phase phosphorylations. Targeted phosphoproteomics in single embryos showed switch-like mitotic phosphorylation of diverse protein complexes. The majority of cell cycle-regulated phosphosites occurred in CDK consensus motifs, and 72% located to intrinsically disordered regions. Dynamically phosphorylated proteins, and documented substrates of cell cycle kinases, are significantly more disordered than phosphoproteins in general. Furthermore, 30-50% are components of membraneless organelles. Our results suggest that phosphorylation of intrinsically disordered proteins by cell cycle kinases, particularly CDKs, allows switch-like mitotic cellular reorganisation.

scholarly journals The molecular mechanism of nuclear transport revealed by atomic-scale measurements

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Loren E Hough ◽  
Kaushik Dutta ◽  
Samuel Sparks ◽  
Deniz B Temel ◽  
Alia Kamal ◽  
...  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Atomic Scale ◽  
Disordered Proteins ◽  
Nuclear Pore ◽  
Resonance Spectroscopy ◽  
Nuclear Pore Complexes ◽  
Selective Filter ◽  
Intrinsically Disordered ◽  
Cellular Environment ◽  
Pore Complexes

Nuclear pore complexes (NPCs) form a selective filter that allows the rapid passage of transport factors (TFs) and their cargoes across the nuclear envelope, while blocking the passage of other macromolecules. Intrinsically disordered proteins (IDPs) containing phenylalanyl-glycyl (FG)-rich repeats line the pore and interact with TFs. However, the reason that transport can be both fast and specific remains undetermined, through lack of atomic-scale information on the behavior of FGs and their interaction with TFs. We used nuclear magnetic resonance spectroscopy to address these issues. We show that FG repeats are highly dynamic IDPs, stabilized by the cellular environment. Fast transport of TFs is supported because the rapid motion of FG motifs allows them to exchange on and off TFs extremely quickly through transient interactions. Because TFs uniquely carry multiple pockets for FG repeats, only they can form the many frequent interactions needed for specific passage between FG repeats to cross the NPC.

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 Dynamical Oligomerisation of Histidine Rich Intrinsically Disordered Proteins Is Regulated through Zinc-Histidine Interactions

Biomolecules ◽  
2019 ◽  
Vol 9 (5) ◽  
pp. 168 ◽  
Author(s):  
Carolina Cragnell ◽  
Lasse Staby ◽  
Samuel Lenton ◽  
Birthe Kragelund ◽  
Marie Skepö
Keyword(s):  
Nuclear Magnetic Resonance ◽  
Intrinsically Disordered Proteins ◽  
Divalent Cations ◽  
Disordered Proteins ◽  
Resonance Spectroscopy ◽  
Binding Motifs ◽  
Histatin 5 ◽  
X Ray ◽  
Intrinsically Disordered ◽  
X Ray Scattering

Intrinsically disordered proteins (IDPs) can form functional oligomers and in some cases, insoluble disease related aggregates. It is therefore vital to understand processes and mechanisms that control pathway distribution. Divalent cations including Zn2+ can initiate IDP oligomerisation through the interaction with histidine residues but the mechanisms of doing so are far from understood. Here we apply a multi-disciplinary approach using small angle X-ray scattering, nuclear magnetic resonance spectroscopy, calorimetry and computations to show that that saliva protein Histatin 5 forms highly dynamic oligomers in the presence of Zn2+. The process is critically dependent upon interaction between Zn2+ ions and distinct histidine rich binding motifs which allows for thermodynamic switching between states. We propose a molecular mechanism of oligomerisation, which may be generally applicable to other histidine rich IDPs. Finally, as Histatin 5 is an important saliva component, we suggest that Zn2+ induced oligomerisation may be crucial for maintaining saliva homeostasis.

scholarly journals Physical Background of the Disordered Nature of “Mutual Synergetic Folding” Proteins

2018 ◽  
Vol 19 (11) ◽  
pp. 3340 ◽  
Author(s):  
Csaba Magyar ◽  
Anikó Mentes ◽  
Erzsébet Fichó ◽  
Miklós Cserző ◽  
István Simon
Keyword(s):  
Contact Surface ◽  
Driving Force ◽  
Structural Variation ◽  
Intrinsically Disordered Proteins ◽  
Main Chain ◽  
Protein Complexes ◽  
3D Structure ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Physical Background

Intrinsically disordered proteins (IDPs) lack a well-defined 3D structure. Their disordered nature enables them to interact with several other proteins and to fulfil their vital biological roles, in most cases after coupled folding and binding. In this paper, we analyze IDPs involved in a new mechanism, mutual synergistic folding (MSF). These proteins define a new subset of IDPs. Recently we collected information on these complexes and created the Mutual Folding Induced by Binding (MFIB) database. These protein complexes exhibit considerable structural variation, and almost half of them are homodimers, but there is a significant amount of heterodimers and various kinds of oligomers. In order to understand the basic background of the disordered character of the monomers found in MSF complexes, the simplest part of the MFIB database, the homodimers are analyzed here. We conclude that MFIB homodimeric proteins have a larger solvent-accessible main-chain surface area on the contact surface of the subunits, when compared to globular homodimeric proteins. The main driving force of the dimerization is the mutual shielding of the water-accessible backbones and the formation of extra intermolecular interactions.

scholarly journals Structural disorder and modular organization in Paramyxovirinae N and P

2003 ◽  
Vol 84 (12) ◽  
pp. 3239-3252 ◽  
Author(s):  
David Karlin ◽  
François Ferron ◽  
Bruno Canard ◽  
Sonia Longhi
Keyword(s):  
Measles Virus ◽  
Intrinsically Disordered Proteins ◽  
Intrinsic Disorder ◽  
Structural Disorder ◽  
Disordered Proteins ◽  
Modular Organization ◽  
Intrinsically Disordered ◽  
Physico Chemical ◽  
Chemical Concepts ◽  
Nucleoprotein N

The existence and extent of disorder within the replicative complex (N, P and the polymerase, L) of Paramyxovirinae were investigated, drawing on the discovery that the N-terminal moiety of the phosphoprotein (P) and the C-terminal moiety of the nucleoprotein (N) of measles virus are intrinsically unstructured. We show that intrinsic disorder is a widespread property within Paramyxovirinae N and P, using a combination of different computational approaches relying on different physico-chemical concepts. Notably, experimental support that has often gone unnoticed for most of the predictions has been found in the literature. Identification of disordered regions allows the unveiling of a common organization in all Paramyxovirinae P, which are composed of six modules defined on the basis of structure or sequence conservation. The possible functional significance of intrinsic disorder is discussed in the light of experimental data, which show that unstructured regions of P and N are involved in numerous interactions with several protein and protein–RNA partners. This study provides a contribution to the rather poorly investigated field of intrinsically disordered proteins and helps in targeting protein domains for structural studies.

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