scholarly journals E2s: structurally economical and functionally replete

2010 ◽  
Vol 433 (1) ◽  
pp. 31-42 ◽  
Author(s):  
Dawn M. Wenzel ◽  
Kate E. Stoll ◽  
Rachel E. Klevit
Keyword(s):  
Protein Interactions ◽  
Catalytic Domain ◽  
Three Dimensional ◽  
Protein Protein Interactions ◽  
Post Translational Modification ◽  
Cellular Regulation ◽  
Substrate Modification ◽  
Binding Partners ◽  
Unique Protein ◽  
Disease Pathways

Ubiquitination is a post-translational modification pathway involved in myriad cellular regulation and disease pathways. The Ub (ubiquitin) transfer cascade requires three enzyme activities: a Ub-activating (E1) enzyme, a Ub-conjugating (E2) enzyme, and a Ub ligase (E3). Because the E2 is responsible both for E3 selection and substrate modification, E2s function at the heart of the Ub transfer pathway and are responsible for much of the diversity of Ub cellular signalling. There are currently over 90 three-dimensional structures for E2s, both alone and in complex with protein binding partners, providing a wealth of information regarding how E2s are recognized by a wide variety of proteins. In the present review, we describe the prototypical E2–E3 interface and discuss limitations of current methods to identify cognate E2–E3 partners. We present non-canonical E2–protein interactions and highlight the economy of E2s in their ability to facilitate many protein–protein interactions at nearly every surface on their relatively small and compact catalytic domain. Lastly, we compare the structures of conjugated E2~Ub species, their unique protein interactions and the mechanistic insights provided by species that are poised to transfer Ub.

scholarly journals Dual functionality of O -GlcNAc transferase is required for Drosophila development

Open Biology ◽  
2015 ◽  
Vol 5 (12) ◽  
pp. 150234 ◽  
Author(s):  
Daniel Mariappa ◽  
Xiaowei Zheng ◽  
Marianne Schimpl ◽  
Olawale Raimi ◽  
Andrew T. Ferenbach ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Rational Design ◽  
Catalytic Domain ◽  
Protein Protein Interactions ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
Tetratricopeptide Repeats ◽  
Sex Combs ◽  
Glcnac Transferase ◽  
Activity Dependent

Post-translational modification of intracellular proteins with O -linked N -acetylglucosamine ( O -GlcNAc) catalysed by O -GlcNAc transferase (OGT) has been linked to regulation of diverse cellular functions. OGT possesses a C-terminal glycosyltransferase catalytic domain and N-terminal tetratricopeptide repeats that are implicated in protein–protein interactions. Drosophila OGT ( Dm OGT) is encoded by super sex combs ( sxc ), mutants of which are pupal lethal. However, it is not clear if this phenotype is caused by reduction of O -GlcNAcylation. Here we use a genetic approach to demonstrate that post-pupal Drosophila development can proceed with negligible OGT catalysis, while early embryonic development is OGT activity-dependent. Structural and enzymatic comparison between human OGT (hOGT) and Dm OGT informed the rational design of Dm OGT point mutants with a range of reduced catalytic activities. Strikingly, a severely hypomorphic OGT mutant complements sxc pupal lethality. However, the hypomorphic OGT mutant-rescued progeny do not produce F2 adults, because a set of Hox genes is de-repressed in F2 embryos, resulting in homeotic phenotypes. Thus, OGT catalytic activity is required up to late pupal stages, while further development proceeds with severely reduced OGT activity.

Identification of binding partners of CsaA - an archaeal chaperonic pro-tein of Picrophilus torridus

2020 ◽  
Vol 27 ◽  
Author(s):  
Neelja Singhal ◽  
Archana Sharma ◽  
Manisha Aswal ◽  
Nirpendra Singh ◽  
Manish Kumar ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Citrate Synthase ◽  
Elongation Factor ◽  
Trna Synthetase ◽  
Strong Interactions ◽  
Beta Chain ◽  
Protein Protein Interactions ◽  
Uncharacterized Protein ◽  
Binding Partners ◽  
Picrophilus Torridus

Background:: CsaA is among the few chaperones which are present in both bacteria and archaea, but absent in eukaryotes. There are no reports on interactome analysis of CsaA from archaea, till date. Identification of binding partners of CsaA might be helpful in understanding CsaA-associated processes in Picrophilus torridus– an extreme thermoaci-dophilic euryarchaeon. Objectives:: The present study was conducted to identify the binding partners of CsaA of P. torridus (PtCsaA). Methods:: The binding partners of PtCsaA were isolated and identified using a pull down assay and liquid chromatography-mass spectrometry (LC-MS). Results:: The results revealed twelve potential binding partners of CsaA. These were thermosome subunits (Q6KZS2 and Q6L132), nascent polypeptide-associated complex protein (Q6L1N3), elongation factor 1-alpha (Q6L202), uncharacterized protein (Q6L0Y6), citrate synthase (Q6L0M8), asparaginyl-tRNA synthetase (Q6L0M5), succinyl-CoA synthetase beta chain (Q6L0B4), pyruvate ferredoxin oxidoreductase alpha and beta chain proteins (Q6KZA7 and Q6KZA6, respectively), malate dehydrogenase (Q6L0C3) and reversed fumarylacetoacetase (Q6KZ97). Functional categorization revealed that of these, six proteins were involved in energy metabolic pathways, three were archaeal chaperones, two were involved in trans-lation and one might be a transcription regulator. STRING-based analysis of the protein-protein interactions of the experi-mental interactome revealed strong interactions among them. Conclusion:: PtCsaA might be a multifaceted protein which besides translation might also play important role in metabolic processes of P. torridus. However, further experiments investigating the binding partners of CsaA in other archaea are re-quired for a better understanding of CsaA-associated processes in archaea.

scholarly journals A unified resource and configurable model of the synapse proteome and its role in disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Oksana Sorokina ◽  
Colin Mclean ◽  
Mike D. R. Croning ◽  
Katharina F. Heil ◽  
Emilia Wysocka ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Synaptic Proteins ◽  
Protein Protein Interactions ◽  
Network Resource ◽  
Unique Protein ◽  
Co Morbidity ◽  
Genes Encoding ◽  
Protein Components ◽  
Accessible Format ◽  
Neuronal Disorders

AbstractGenes encoding synaptic proteins are highly associated with neuronal disorders many of which show clinical co-morbidity. We integrated 58 published synaptic proteomic datasets that describe over 8000 proteins and combined them with direct protein–protein interactions and functional metadata to build a network resource that reveals the shared and unique protein components that underpin multiple disorders. All the data are provided in a flexible and accessible format to encourage custom use.

scholarly journals Androgen signaling uses a writer and a reader of ADP-ribosylation to regulate protein complex assembly

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Chun-Song Yang ◽  
Kasey Jividen ◽  
Teddy Kamata ◽  
Natalia Dworak ◽  
Luke Oostdyk ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Interactions ◽  
Prostate Cancer Cells ◽  
Protein Protein Interactions ◽  
Post Translational Modification ◽  
Complex Assembly ◽  
Adp Ribosylation ◽  
Signaling Axis ◽  
Regulate Protein ◽  
Protein Complex Assembly

AbstractAndrogen signaling through the androgen receptor (AR) directs gene expression in both normal and prostate cancer cells. Androgen regulates multiple aspects of the AR life cycle, including its localization and post-translational modification, but understanding how modifications are read and integrated with AR activity has been difficult. Here, we show that ADP-ribosylation regulates AR through a nuclear pathway mediated by Parp7. We show that Parp7 mono-ADP-ribosylates agonist-bound AR, and that ADP-ribosyl-cysteines within the N-terminal domain mediate recruitment of the E3 ligase Dtx3L/Parp9. Molecular recognition of ADP-ribosyl-cysteine is provided by tandem macrodomains in Parp9, and Dtx3L/Parp9 modulates expression of a subset of AR-regulated genes. Parp7, ADP-ribosylation of AR, and AR-Dtx3L/Parp9 complex assembly are inhibited by Olaparib, a compound used clinically to inhibit poly-ADP-ribosyltransferases Parp1/2. Our study reveals the components of an androgen signaling axis that uses a writer and reader of ADP-ribosylation to regulate protein-protein interactions and AR activity.

scholarly journals The Protein Interactome of Glycolysis in Escherichia coli

Proteomes ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 16
Author(s):  
Shomeek Chowdhury ◽  
Stephen Hepper ◽  
Mudassir K. Lodi ◽  
Milton H. Saier ◽  
Peter Uetz
Keyword(s):  
Escherichia Coli ◽  
Protein Interactions ◽  
Allosteric Regulation ◽  
Glycolytic Enzymes ◽  
Protein Protein Interactions ◽  
Post Translational Modification ◽  
Interacting Protein ◽  
E Coli ◽  
Protein Interactome ◽  
The Impact

Glycolysis is regulated by numerous mechanisms including allosteric regulation, post-translational modification or protein-protein interactions (PPI). While glycolytic enzymes have been found to interact with hundreds of proteins, the impact of only some of these PPIs on glycolysis is well understood. Here we investigate which of these interactions may affect glycolysis in E. coli and possibly across numerous other bacteria, based on the stoichiometry of interacting protein pairs (from proteomic studies) and their conservation across bacteria. We present a list of 339 protein-protein interactions involving glycolytic enzymes but predict that ~70% of glycolytic interactors are not present in adequate amounts to have a significant impact on glycolysis. Finally, we identify a conserved but uncharacterized subset of interactions that are likely to affect glycolysis and deserve further study.

scholarly journals Activation and assembly of the NADPH oxidase: a structural perspective

2005 ◽  
Vol 386 (3) ◽  
pp. 401-416 ◽  
Author(s):  
Yvonne GROEMPING ◽  
Katrin RITTINGER
Keyword(s):  
Nadph Oxidase ◽  
Protein Interactions ◽  
Structural Information ◽  
Three Dimensional ◽  
Protein Protein Interactions ◽  
Crucial Component ◽  
Enzyme Subunits ◽  
Membrane Components ◽  
Inhibitory Interactions ◽  
Encompassing Model

The NADPH oxidase of professional phagocytes is a crucial component of the innate immune response due to its fundamental role in the production of reactive oxygen species that act as powerful microbicidal agents. The activity of this multi-protein enzyme is dependent on the regulated assembly of the six enzyme subunits at the membrane where oxygen is reduced to superoxide anions. In the resting state, four of the enzyme subunits are maintained in the cytosol, either through auto-inhibitory interactions or through complex formation with accessory proteins that are not part of the active enzyme complex. Multiple inputs are required to disrupt these inhibitory interactions and allow translocation to the membrane and association with the integral membrane components. Protein interaction modules are key regulators of NADPH oxidase assembly, and the protein–protein interactions mediated via these domains have been the target of numerous studies. Many models have been put forward to describe the intricate network of reversible protein interactions that regulate the activity of this enzyme, but an all-encompassing model has so far been elusive. An important step towards an understanding of the molecular basis of NADPH oxidase assembly and activity has been the recent solution of the three-dimensional structures of some of the oxidase components. We will discuss these structures in the present review and attempt to reconcile some of the conflicting models on the basis of the structural information available.

scholarly journals Protein-protein docking using learned three-dimensional representations

2019 ◽  
Author(s):  
Georgy Derevyanko ◽  
Guillaume Lamoureux
Keyword(s):  
Protein Interactions ◽  
Network Architecture ◽  
Protein Complexes ◽  
Three Dimensional ◽  
Spatial Arrangement ◽  
Protein Docking ◽  
Protein Protein Interactions ◽  
Translational Invariance ◽  
Shape Complementarity ◽  
Spatial Features

AbstractProtein-protein interactions are determined by a number of hard-to-capture features related to shape complementarity, electrostatics, and hydrophobicity. These features may be intrinsic to the protein or induced by the presence of a partner. A conventional approach to protein-protein docking consists in engineering a small number of spatial features for each protein, and in minimizing the sum of their correlations with respect to the spatial arrangement of the two proteins. To generalize this approach, we introduce a deep neural network architecture that transforms the raw atomic densities of each protein into complex three-dimensional representations. Each point in the volume containing the protein is described by 48 learned features, which are correlated and combined with the features of a second protein to produce a score dependent on the relative position and orientation of the two proteins. The architecture is based on multiple layers of SE(3)-equivariant convolutional neural networks, which provide built-in rotational and translational invariance of the score with respect to the structure of the complex. The model is trained end-to-end on a set of decoy conformations generated from 851 nonredundant protein-protein complexes and is tested on data from the Protein-Protein Docking Benchmark Version 4.0.

Tyrosine-O-sulfation is a widespread affinity enhancer among thrombin interactors

2022 ◽  
Author(s):  
Jorge Ripoll-Rozada ◽  
Joshua W. C. Maxwell ◽  
Richard J. Payne ◽  
Pedro José Barbosa Pereira
Keyword(s):  
Protein Interactions ◽  
Secretory Pathway ◽  
Serine Proteinase ◽  
Blood Feeding ◽  
Thrombin Inhibitor ◽  
Protein Protein Interactions ◽  
Post Translational Modification ◽  
Human Fibrinogen ◽  
Clotting Cascade ◽  
Bona Fide

Tyrosine-O-sulfation is a common post-translational modification (PTM) of proteins following the cellular secretory pathway. First described in human fibrinogen, tyrosine-O-sulfation has long been associated with the modulation of protein–protein interactions in several physiological processes. A number of relevant interactions for hemostasis are largely dictated by this PTM, many of which involving the serine proteinase thrombin (FIIa), a central player in the blood-clotting cascade. Tyrosine sulfation is not limited to endogenous FIIa ligands and has also been found in hirudin, a well-known and potent thrombin inhibitor from the medicinal leech, Hirudo medicinalis. The discovery of hirudin led to successful clinical application of analogs of leech-inspired molecules, but also unveiled several other natural thrombin-directed anticoagulant molecules, many of which undergo tyrosine-O-sulfation. The presence of this PTM has been shown to enhance the anticoagulant properties of these peptides from a range of blood-feeding organisms, including ticks, mosquitos and flies. Interestingly, some of these molecules display mechanisms of action that mimic those of thrombin's bona fide substrates.

scholarly journals Chemical Decorations of “MARs” Residents in Orchestrating Eukaryotic Gene Regulation

2020 ◽  
Vol 8 ◽  
Author(s):  
Tanaya Roychowdhury ◽  
Samit Chattopadhyay
Keyword(s):  
Gene Regulation ◽  
Conformational Changes ◽  
Protein Interactions ◽  
Protein Function ◽  
Functional Outcomes ◽  
Three Dimensional ◽  
Limited Information ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
3D Matrix

Genome organization plays a crucial role in gene regulation, orchestrating multiple cellular functions. A meshwork of proteins constituting a three-dimensional (3D) matrix helps in maintaining the genomic architecture. Sequences of DNA that are involved in tethering the chromatin to the matrix are called scaffold/matrix attachment regions (S/MARs), and the proteins that bind to these sequences and mediate tethering are termed S/MAR-binding proteins (S/MARBPs). The regulation of S/MARBPs is important for cellular functions and is altered under different conditions. Limited information is available presently to understand the structure–function relationship conclusively. Although all S/MARBPs bind to DNA, their context- and tissue-specific regulatory roles cannot be justified solely based on the available information on their structures. Conformational changes in a protein lead to changes in protein–protein interactions (PPIs) that essentially would regulate functional outcomes. A well-studied form of protein regulation is post-translational modification (PTM). It involves disulfide bond formation, cleavage of precursor proteins, and addition or removal of low-molecular-weight groups, leading to modifications like phosphorylation, methylation, SUMOylation, acetylation, PARylation, and ubiquitination. These chemical modifications lead to varied functional outcomes by mechanisms like modifying DNA–protein interactions and PPIs, altering protein function, stability, and crosstalk with other PTMs regulating subcellular localizations. S/MARBPs are reported to be regulated by PTMs, thereby contributing to gene regulation. In this review, we discuss the current understanding, scope, disease implications, and future perspectives of the diverse PTMs regulating functions of S/MARBPs.

Sign in / Sign up

Export Citation Format

Share Document