Browse
Submit Data
Databases
API
Help

Dataset Information

29 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Toward an Understanding of the Structural and Mechanistic Aspects of Protein-Protein Interactions in 2-Oxoacid Dehydrogenase Complexes.

ABSTRACT: The 2-oxoglutarate dehydrogenase complex (OGDHc) is a key enzyme in the tricarboxylic acid (TCA) cycle and represents one of the major regulators of mitochondrial metabolism through NADH and reactive oxygen species levels. The OGDHc impacts cell metabolic and cell signaling pathways through the coupling of 2-oxoglutarate metabolism to gene transcription related to tumor cell proliferation and aging. DHTKD1 is a gene encoding 2-oxoadipate dehydrogenase (E1a), which functions in the L-lysine degradation pathway. The potentially damaging variants in DHTKD1 have been associated to the (neuro) pathogenesis of several diseases. Evidence was obtained for the formation of a hybrid complex between the OGDHc and E1a, suggesting a potential cross talk between the two metabolic pathways and raising fundamental questions about their assembly. Here we reviewed the recent findings and advances in understanding of protein-protein interactions in OGDHc and 2-oxoadipate dehydrogenase complex (OADHc), an understanding that will create a scaffold to help design approaches to mitigate the effects of diseases associated with dysfunction of the TCA cycle or lysine degradation. A combination of biochemical, biophysical and structural approaches such as chemical cross-linking MS and cryo-EM appears particularly promising to provide vital information for the assembly of 2-oxoacid dehydrogenase complexes, their function and regulation.

SUBMITTER: Nemeria NS

PROVIDER: S-EPMC8146983 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

A structural phylogeny for understanding 2-oxoacid oxidoreductase function.

Project description:2-Oxoacid:ferredoxin oxidoreductases (OFORs) are essential enzymes in microbial one-carbon metabolism. They use thiamine pyrophosphate to reversibly cleave carbon-carbon bonds, generating low potential (∼-500mV) electrons. Crystallographic analysis of a recently discovered OFOR, an oxalate oxidoreductase (OOR), has provided a second view of OFOR architecture and active site composition. Using these recent structural data along with the previously determined structures of pyruvate:ferredoxin oxidoreductase, structure-function relationships in this superfamily have been expanded and re-evaluated. Additionally, structural motifs have been defined that better serve to distinguish one OFOR subfamily from another and potentially uncover novel OFORs.

| S-EPMC5381805 | biostudies-literature

Toward a molecular understanding of nanoparticle-protein interactions.

Project description:Wherever nanoparticles (NPs) come in contact with a living organism, physical and chemical interactions take place between the surfaces of the NPs and biomatter, in particular proteins. When NP are exposed to biological fluids, an adsorption layer of proteins, a "protein corona" forms around the NPs. Consequently, living systems interact with the protein-coated NP rather than with a bare NP. To anticipate biological responses to NPs, we thus require comprehensive knowledge of the interactions at the bio-nano interface. In recent years, a wide variety of biophysical techniques have been employed to elucidate mechanistic aspects of NP-protein interactions. In this brief review, we present the latest findings regarding the composition of the protein corona as it forms on NPs in the blood stream. We also discuss molecular aspects of this adsorption layer and its time evolution. The current state of knowledge is summarized, and issues that still need to be addressed to further advance our understanding of NP-protein interactions are identified.

| S-EPMC5418382 | biostudies-literature

Three-dimensional structural aspects of protein-polysaccharide interactions.

Project description:Linear polysaccharides are typically composed of repeating mono- or disaccharide units and are ubiquitous among living organisms. Polysaccharide diversity arises from chain-length variation, branching, and additional modifications. Structural diversity is associated with various physiological functions, which are often regulated by cognate polysaccharide-binding proteins. Proteins that interact with linear polysaccharides have been identified or developed, such as galectins and polysaccharide-specific antibodies, respectively. Currently, data is accumulating on the three-dimensional structure of polysaccharide-binding proteins. These proteins are classified into two types: exo-type and endo-type. The former group specifically interacts with the terminal units of polysaccharides, whereas the latter with internal units. In this review, we describe the structural aspects of exo-type and endo-type protein-polysaccharide interactions. Further, we discuss the structural basis for affinity and specificity enhancement in the face of inherently weak binding interactions.

| S-EPMC3975366 | biostudies-literature

A perspective on structural and mechanistic aspects of protein O-fucosylation.

Project description:Protein O-fucosylation is an important post-translational modification (PTM) found in cysteine-rich repeats in proteins. Protein O-fucosyltransferases 1 and 2 (PoFUT1 and PoFUT2) are the enzymes responsible for this PTM and selectively glycosylate specific residues in epidermal growth factor-like (EGF) repeats and thrombospondin type I repeats (TSRs), respectively. Within the past six years, crystal structures of both enzymes have been reported, revealing important information on how they recognize protein substrates and achieve catalysis. Here, the structural information available today is summarized and how PoFUT1 and PoFUT2 employ different catalytic mechanisms is discussed.

| S-EPMC6096484 | biostudies-literature

Protein interactions from complexes: a structural perspective.

Project description:By combining crystallographic information with protein-interaction data obtained through traditional experimental means, this paper determines the most appropriate method for generating protein-interaction networks that incorporate data derived from protein complexes. We propose that a combined method should be considered; in which complexes composed of five chains or less are decomposed using the matrix model, whereas the spoke model is used to derive pairwise interactions for those with six chains or more. The results presented here should improve the accuracy and relevance of studies investigating the topology of protein-interaction networks.

| S-EPMC1838958 | biostudies-literature

Structural and mechanistic aspects influencing the ADAM10-mediated shedding of the prion protein.

Project description:Proteolytic processing of the prion protein (PrPC) by endogenous proteases generates bioactive membrane-bound and soluble fragments which may help to explain the pleiotropic roles of this protein in the nervous system and in brain diseases. Shedding of almost full-length PrPC into the extracellular space by the metalloprotease ADAM10 is of peculiar relevance since soluble PrP stimulates axonal outgrowth and is protective in neurodegenerative conditions such as Alzheimer’s and prion disease. However, molecular determinates and mechanisms regulating the shedding of PrP are entirely unknown.We produced an antibody recognizing the neo-epitope of shed PrP generated by ADAM10 in biological samples and used it to study structural and mechanistic aspects affecting the shedding. For this, we investigated genetically modified cellular and murine models by biochemical and morphological approaches.We show that the novel antibody specifically detects shed PrP in cell culture supernatants and murine brain. We demonstrate that ADAM10 is the exclusive sheddase of PrPC in the nervous system and reveal that the glycosylation state and type of membrane-anchorage of PrPC severely affect its shedding. Furthermore, we provide evidence that PrP shedding can be modulated by pharmacological inhibition and stimulation and present data suggesting that shedding is a relevant part of a compensatory network ensuring PrPC homeostasis of the cell.With the new antibody, our study introduces a new tool to reliably investigate PrP-shedding. In addition, this study provides novel and important insight into the regulation of this cleavage event, which is likely to be relevant for diagnostic and therapeutic approaches even beyond neurodegeneration.

| S-EPMC5889536 | biostudies-other

Structural and mechanistic aspects of carotenoid cleavage dioxygenases (CCDs).

Project description:Carotenoid cleavage dioxygenases (CCDs) comprise a superfamily of mononuclear non-heme iron proteins that catalyze the oxygenolytic fission of alkene bonds in carotenoids to generate apocarotenoid products. Some of these enzymes exhibit additional activities such as carbon skeleton rearrangement and trans-cis isomerization. The group also includes a subfamily of enzymes that split the interphenyl alkene bond in molecules such as resveratrol and lignostilbene. CCDs are involved in numerous biological processes ranging from production of light-sensing chromophores to degradation of lignin derivatives in pulping waste sludge. These enzymes exhibit unique features that distinguish them from other families of non-heme iron enzymes. The distinctive properties and biological importance of CCDs have stimulated interest in their modes of catalysis. Recent structural, spectroscopic, and computational studies have helped clarify mechanistic aspects of CCD catalysis. Here, we review these findings emphasizing common and unique properties of CCDs that enable their variable substrate specificity and regioselectivity. This article is part of a Special Issue entitled Carotenoids recent advances in cell and molecular biology edited by Johannes von Lintig and Loredana Quadro.

| S-EPMC7308199 | biostudies-literature

Computational large-scale mapping of protein-protein interactions using structural complexes.

Project description:Although the identification of protein interactions by high-throughput methods progresses at a fast pace, "interactome" datasets still suffer from high rates of false positives and low coverage. To map the interactome of any organism, this unit presents a computational framework to predict protein-protein or gene-gene interactions utilizing experimentally determined evidence of structural complexes, atomic details of binding interfaces and evolutionary conservation.

| S-EPMC3920302 | biostudies-literature

Toward Small-Molecule Inhibition of Protein-Protein Interactions: General Aspects and Recent Progress in Targeting Costimulatory and Coinhibitory (Immune Checkpoint) Interactions.

Project description:Protein-Protein Interactions (PPIs) that are part of the costimulatory and coinhibitory (immune checkpoint) signaling are critical for adequate T cell response and are important therapeutic targets for immunomodulation. Biologics targeting them have already achieved considerable clinical success in the treatment of autoimmune diseases or transplant recipients (e.g., abatacept, belatacept, and belimumab) as well as cancer (e.g., ipilimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab). In view of such progress, there have been only relatively limited efforts toward developing small-molecule PPI inhibitors (SMPPIIs) targeting these cosignaling interactions, possibly because they, as all other PPIs, are difficult to target by small molecules and were not considered druggable. Nevertheless, substantial progress has been achieved during the last decade. SMPPIIs proving the feasibility of such approaches have been identified through various strategies for a number of cosignaling interactions including CD40-CD40L, OX40-OX40L, BAFFR-BAFF, CD80-CD28, and PD-1-PD-L1s. Here, after an overview of the general aspects and challenges of SMPPII-focused drug discovery, we review them briefly together with relevant structural, immune-signaling, physicochemical, and medicinal chemistry aspects. While so far only a few of these SMPPIIs have shown activity in animal models (DRI-C21045 for CD40-D40L, KR33426 for BAFFR-BAFF) or reached clinical development (RhuDex for CD80-CD28, CA-170 for PD-1-PD-L1), there is proof-of-principle evidence for the feasibility of such approaches in immunomodulation. They can result in products that are easier to develop/ manufacture and are less likely to be immunogenic or encounter postmarket safety events than corresponding biologics, and, contrary to them, can even become orally bioavailable.

| S-EPMC6067980 | biostudies-literature

Toward a mechanistic understanding of Feo-mediated ferrous iron uptake.

Project description:Virtually all organisms require iron and have evolved to obtain this element in free or chelated forms. Under anaerobic or low pH conditions commonly encountered by numerous pathogens, iron predominantly exists in the ferrous (Fe2+) form. The ferrous iron transport (Feo) system is the only widespread mechanism dedicated solely to bacterial ferrous iron import, and this system has been linked to pathogenic virulence, bacterial colonization, and microbial survival. The canonical feo operon encodes for three proteins that comprise the Feo system: FeoA, a small cytoplasmic β-barrel protein; FeoB, a large, polytopic membrane protein with a soluble G-protein domain capable of hydrolyzing GTP; and FeoC, a small, cytoplasmic protein containing a winged-helix motif. While previous studies have revealed insight into soluble and fragmentary domains of the Feo system, the chief membrane-bound component FeoB remains poorly studied. However, recent advances have demonstrated that large quantities of intact FeoB can be overexpressed, purified, and biophysically characterized, revealing glimpses into FeoB function. Two models of full-length FeoB have been published, providing starting points for hypothesis-driven investigations into the mechanism of FeoB-mediated ferrous iron transport. Finally, in vivo studies have begun to shed light on how this system functions as a unique multicomponent complex. In light of these new data, this review will summarize what is known about the Feo system, including recent advancements in FeoB structure and function.

| S-EPMC6051883 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data