scholarly journals A distinct class of plant and animal viral proteins that disrupt mitosis by directly interrupting the mitotic entry switch Wee1-Cdc25-Cdk1

2020 ◽  
Vol 6 (20) ◽  
pp. eaba3418
Author(s):  
Huaibing Jin ◽  
Zhiqiang Du ◽  
Yanjing Zhang ◽  
Judit Antal ◽  
Zongliang Xia ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Viral Proteins ◽  
Plant Viruses ◽  
Amino Acid Residues ◽  
Protein Protein Interactions ◽  
Common Amino Acid ◽  
Mitotic Entry ◽  
Distinct Class ◽  
Barley Yellow Dwarf ◽  
Hiv 1

Many animal viral proteins, e.g., Vpr of HIV-1, disrupt host mitosis by directly interrupting the mitotic entry switch Wee1-Cdc25-Cdk1. However, it is unknown whether plant viruses may use this mechanism in their pathogenesis. Here, we report that the 17K protein, encoded by barley yellow dwarf viruses and related poleroviruses, delays G2/M transition and disrupts mitosis in both host (barley) and nonhost (fission yeast, Arabidopsis thaliana, and tobacco) cells through interrupting the function of Wee1-Cdc25-CDKA/Cdc2 via direct protein-protein interactions and alteration of CDKA/Cdc2 phosphorylation. When ectopically expressed, 17K disrupts the mitosis of cultured human cells, and HIV-1 Vpr inhibits plant cell growth. Furthermore, 17K and Vpr share similar secondary structural feature and common amino acid residues required for interacting with plant CDKA. Thus, our work reveals a distinct class of mitosis regulators that are conserved between plant and animal viruses and play active roles in viral pathogenesis.

Quantitative analysis of the interactions between HIV-1 integrase and retroviral reverse transcriptases

2008 ◽  
Vol 412 (1) ◽  
pp. 163-170 ◽  
Author(s):  
Alon Herschhorn ◽  
Iris Oz-Gleenberg ◽  
Amnon Hizi
Keyword(s):  
Conformational Changes ◽  
Protein Interactions ◽  
Molecular Mechanisms ◽  
Reaction Model ◽  
Protein Protein Interactions ◽  
Common Site ◽  
Leukaemia Virus ◽  
Reverse Transcriptases ◽  
Interaction Kinetics ◽  
Hiv 1

The RT (reverse transcriptase) of HIV-1 interacts with HIV-1 IN (integrase) and inhibits its enzymatic activities. However, the molecular mechanisms underling these interactions are not well understood. In order to study these mechanisms, we have analysed the interactions of HIV-1 IN with HIV-1 RT and with two other related RTs: those of HIV-2 and MLV (murine-leukaemia virus). All three RTs inhibited HIV-1 IN, albeit to a different extent, suggesting a common site of binding that could be slightly modified for each one of the studied RTs. Using surface plasmon resonance technology, which monitors direct protein–protein interactions, we performed kinetic analyses of the binding of HIV-1 IN to these three RTs and observed interesting binding patterns. The interaction of HIV-1 RT with HIV-1 IN was unique and followed a two-state reaction model. According to this model, the initial IN–RT complex formation was followed by a conformational change in the complex that led to an elevation of the total affinity between these two proteins. In contrast, HIV-2 and MLV RTs interacted with IN in a simple bi-molecular manner, without any apparent secondary conformational changes. Interestingly, HIV-1 and HIV-2 RTs were the most efficient inhibitors of HIV-1 IN activity, whereas HIV-1 and MLV RTs showed the highest affinity towards HIV-1 IN. These modes of direct protein interactions, along with the apparent rate constants calculated and the correlations of the interaction kinetics with the capacity of the RTs to inhibit IN activities, are all discussed.

scholarly journals Group I Metabotropic Glutamate Receptors and Interacting Partners: An Update

2022 ◽  
Vol 23 (2) ◽  
pp. 840
Author(s):  
Li-Min Mao ◽  
Alaya Bodepudi ◽  
Xiang-Ping Chu ◽  
John Q. Wang
Keyword(s):  
Synaptic Plasticity ◽  
Protein Interactions ◽  
Metabotropic Glutamate Receptors ◽  
Adaptor Proteins ◽  
Mammalian Brain ◽  
Amino Acid Residues ◽  
Protein Protein Interactions ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Associated Proteins

Group I metabotropic glutamate (mGlu) receptors (mGlu1/5 subtypes) are G protein-coupled receptors and are broadly expressed in the mammalian brain. These receptors play key roles in the modulation of normal glutamatergic transmission and synaptic plasticity, and abnormal mGlu1/5 signaling is linked to the pathogenesis and symptomatology of various mental and neurological disorders. Group I mGlu receptors are noticeably regulated via a mechanism involving dynamic protein–protein interactions. Several synaptic protein kinases were recently found to directly bind to the intracellular domains of mGlu1/5 receptors and phosphorylate the receptors at distinct amino acid residues. A variety of scaffolding and adaptor proteins also interact with mGlu1/5. Constitutive or activity-dependent interactions between mGlu1/5 and their interacting partners modulate trafficking, anchoring, and expression of the receptors. The mGlu1/5-associated proteins also finetune the efficacy of mGlu1/5 postreceptor signaling and mGlu1/5-mediated synaptic plasticity. This review analyzes the data from recent studies and provides an update on the biochemical and physiological properties of a set of proteins or molecules that interact with and thus regulate mGlu1/5 receptors.

scholarly journals Characterization of COMMD protein–protein interactions in NF-κB signalling

2006 ◽  
Vol 398 (1) ◽  
pp. 63-71 ◽  
Author(s):  
Prim de Bie ◽  
Bart van de Sluis ◽  
Ezra Burstein ◽  
Karen J. Duran ◽  
Ruud Berger ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Copper Metabolism ◽  
Nuclear Factor Κb ◽  
Inhibitory Effect ◽  
Protein Family ◽  
Amino Acid Residues ◽  
Protein Protein Interactions ◽  
Necrosis Factor

COMMD [copper metabolism gene MURR1 (mouse U2af1-rs1 region 1) domain] proteins constitute a recently identified family of NF-κB (nuclear factor κB)-inhibiting proteins, characterized by the presence of the COMM domain. In the present paper, we report detailed investigation of the role of this protein family, and specifically the role of the COMM domain, in NF-κB signalling through characterization of protein–protein interactions involving COMMD proteins. The small ubiquitously expressed COMMD6 consists primarily of the COMM domain. Therefore COMMD1 and COMMD6 were analysed further as prototype members of the COMMD protein family. Using specific antisera, interaction between endogenous COMMD1 and COMMD6 is described. This interaction was verified by independent techniques, appeared to be direct and could be detected throughout the whole cell, including the nucleus. Both proteins inhibit TNF (tumour necrosis factor)-induced NF-κB activation in a non-synergistic manner. Mutation of the amino acid residues Trp24 and Pro41 in the COMM domain of COMMD6 completely abolished the inhibitory effect of COMMD6 on TNF-induced NF-κB activation, but this was not accompanied by loss of interaction with COMMD1, COMMD6 or the NF-κB subunit RelA. In contrast with COMMD1, COMMD6 does not bind to IκBα (inhibitory κBα), indicating that both proteins inhibit NF-κB in an overlapping, but not completely similar, manner. Taken together, these data support the significance of COMMD protein–protein interactions and provide new mechanistic insight into the function of this protein family in NF-κB signalling.

Peptides that inhibit HIV-1 integrase by blocking its protein-protein interactions

FEBS Journal ◽  
2012 ◽  
Vol 279 (16) ◽  
pp. 2795-2809 ◽  
Author(s):  
Michal Maes ◽  
Abraham Loyter ◽  
Assaf Friedler
Keyword(s):  
Protein Interactions ◽  
Protein Protein Interactions ◽  
Hiv 1

Interactions in vivo between the proteins of infectious bursal disease virus: capsid protein VP3 interacts with the RNA-dependent RNA polymerase, VP1

Microbiology ◽  
2000 ◽  
Vol 81 (1) ◽  
pp. 209-218 ◽  
Author(s):  
Mirriam G. J. Tacken ◽  
Peter J. M. Rottier ◽  
Arno L. J. Gielkens ◽  
Ben P. H. Peeters
Keyword(s):  
Disease Virus ◽  
Protein Interactions ◽  
Infectious Bursal Disease Virus ◽  
Viral Proteins ◽  
Infectious Bursal Disease ◽  
Transactivation Domain ◽  
Protein Protein Interactions ◽  
Bursal Disease ◽  
Infected Cells

Little is known about the intermolecular interactions between the viral proteins of infectious bursal disease virus (IBDV). By using the yeast two-hybrid system, which allows the detection of protein–protein interactions in vivo, all possible interactions were tested by fusing the viral proteins to the LexA DNA-binding domain and the B42 transactivation domain. A heterologous interaction between VP1 and VP3, and homologous interactions of pVP2, VP3, VP5 and possibly VP1, were found by co-expression of the fusion proteins in Saccharomyces cerevisiae. The presence of the VP1–VP3 complex in IBDV-infected cells was confirmed by co-immunoprecipitation studies. Kinetic analyses showed that the complex of VP1 and VP3 is formed in the cytoplasm and eventually is released into the cell-culture medium, indicating that VP1–VP3 complexes are present in mature virions. In IBDV-infected cells, VP1 was present in two forms of 90 and 95 kDa. Whereas VP3 initially interacted with both the 90 and 95 kDa proteins, later it interacted exclusively with the 95 kDa protein both in infected cells and in the culture supernatant. These results suggest that the VP1–VP3 complex is involved in replication and packaging of the IBDV genome.

Analysis of an engineered plasma kallikrein inhibitor and its effect on contact activation

2010 ◽  
Vol 391 (4) ◽  
Author(s):  
A. Allart Stoop ◽  
Ravi V. Joshi ◽  
Christopher T. Eggers ◽  
Charles S. Craik
Keyword(s):  
Serine Protease ◽  
Protein Interactions ◽  
Phage Library ◽  
Plasma Kallikrein ◽  
Amino Acid Residues ◽  
Protein Protein Interactions ◽  
Contact Activation ◽  
Kallikrein Inhibitor ◽  
Membrane Type ◽  
Opposing Effects

AbstractEngineering of protein-protein interactions is used to enhance the affinity or specificity of proteins, such as antibodies or protease inhibitors, for their targets. However, fully diversifying all residues in a protein-protein interface is often unfeasible. Therefore, we limited our phage library for the serine protease inhibitor ecotin by restricting it to only tetranomial diversity and then targeted all 20 amino acid residues involved in protein recognition. This resulted in a high-affinity and highly specific plasma kallikrein inhibitor, ecotin-Pkal. To validate this approach we dissected the energetic contributions of each wild type (wt) or mutated surface loop to the binding of either plasma kallikrein (PKal) or membrane-type serine protease 1. The analysis demonstrated that a mutation in one loop has opposing effects depending on the sequence of surrounding loops. This finding stresses the cooperative nature of loop-loop interactions and justifies targeting multiple loops with a limited diversity. In contrast to ecotin wt, the specific loop combination of ecotin-Pkal discriminates the subtle structural differences between the active enzymes, PKal and Factor XIIa, and their respective zymogen forms. We used ecotin-Pkal to specifically inhibit contact activation of human plasma at the level mediated by plasma kallikrein.

Cardiac hypertrophy and altered β-adrenergic signaling in transgenic mice that express the amino terminus of β-ARK1

2003 ◽  
Vol 285 (5) ◽  
pp. H2201-H2211 ◽  
Author(s):  
Janelle R. Keys ◽  
Emily A. Greene ◽  
Chris J. Cooper ◽  
Sathyamangla V. Naga Prasad ◽  
Howard A. Rockman ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Cardiac Hypertrophy ◽  
Protein Interactions ◽  
Amino Terminus ◽  
Amino Acid Residues ◽  
Protein Protein Interactions ◽  
Gpcr Signaling ◽  
Amino Terminal ◽  
G Protein Coupled

The G protein-coupled receptor (GPCR) kinase β-adrenergic receptor (β-AR) kinase-1 (β-ARK1) is elevated during heart failure; however, its role is not fully understood. β-ARK1 contains several domains that are capable of protein-protein interactions that may play critical roles in the regulation of GPCR signaling. In this study, we developed a novel line of transgenic mice that express an amino-terminal peptide of β-ARK1 that is comprised of amino acid residues 50–145 (β-ARKnt) in the heart to determine whether this domain has any functional significance in vivo. Surprisingly, the β-ARKnt transgenic mice presented with cardiac hypertrophy. Our data suggest that the phenotype was driven via an enhanced β-AR system, as β-ARKnt mice had elevated cardiac β-AR density. Moreover, administration of a β-AR antagonist reversed hypertrophy in these mice. Interestingly, signaling through the β-AR in response to agonist stimulation was not enhanced in these mice. Thus the amino terminus of β-ARK1 appears to be critical for normal β-AR regulation in vivo, which further supports the hypothesis that β-ARK1 plays a key role in normal and compromised cardiac GPCR signaling.

Pharmacophore-Based Discovery of Small-Molecule Inhibitors of Protein-Protein Interactions between HIV-1 Integrase and Cellular Cofactor LEDGF/p75

ChemMedChem ◽  
2009 ◽  
Vol 4 (8) ◽  
pp. 1311-1316 ◽  
Author(s):  
Laura De Luca ◽  
Maria Letizia Barreca ◽  
Stefania Ferro ◽  
Frauke Christ ◽  
Nunzio Iraci ◽  
...  
Keyword(s):  
Small Molecule ◽  
Protein Interactions ◽  
Small Molecule Inhibitors ◽  
Protein Protein Interactions ◽  
Cellular Cofactor ◽  
Hiv 1
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