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PubMed2026

Dual proximity-based interactome mapping of FKBP51 and FKBP52 uncovers shared metabolic networks.

The 51 kDa FK506-binding protein (FKBP51) has been studied for its involvement in regulating multiple biological systems, particularly as a regulator of steroid hormone receptors, but roles in metabolism, pain response, cell survival, protein turnover, autophagy, immune response, and insulin signaling have also been described. Genetic variants of FKBP51 are associated with various stress-related mental disorders. While recent research has clarified aspects of these processes, the complete range of FKBP51 interactions remains undetermined. FKBP52, a closely related homolog, also affects similar pathways. Recent studies have identified new protein partners for FKBP51 and FKBP52, suggesting an even broader interactome with transient associations. To further characterize interactions, TurboID-based proximity labeling was performed in HeLa cells. Proteomic analysis confirmed known FKBP51 and FKBP52 interactions, while also identifying additional shared and unique binding partners with strong enrichment in metabolic pathways, amino acid biosynthesis, and carbon metabolism. Although FKBP51 and FKBP52 proximal proteins were primarily cytosolic, FKBP51 showed additional associations with exosomal proteins while FKBP52 engaged with additional nuclear proteins. These findings highlight the overlapping roles in metabolic signaling and differentiate pathway-specific partners.

Tacrolimus Binding Proteins↗
PubMed2025

Spatiotemporally resolved GPCR interactome uncovers unique mediators of receptor agonism.

Cellular signaling by membrane G protein-coupled receptors (GPCRs) is governed by a complex and diverse array of mechanisms. The dynamics of a GPCR interactome, as it evolves over time and space in response to an agonist, provide a unique perspective on pleiotropic signaling decoding and functional selectivity at the cellular level. In this study, we utilized proximity-based APEX2 proteomics to investigate the interaction network of the luteinizing hormone receptor (LHR) on a minute-to-minute timescale. We developed an analytical approach that integrates quantitative multiplexed proteomics with temporal reference profiles, creating a platform to identify the proteomic environment of APEX2-tagged LHR at the nanometer scale. LHR activity is finely regulated spatially, leading to the identification of putative interactors, including the Ras-related GTPase RAP2B, which modulate both receptor signaling and post-endocytic trafficking. This work provides a valuable resource for spatiotemporal nanodomain mapping of LHR interactors across subcellular compartments.

Humans↗
PubMed2026

Subcellular proteomic analysis of the DDR2 interactome in a neuronal cell model exposed to Aβ42.

Receptor tyrosine kinases (RTKs) are increasingly understood to signal beyond the plasma membrane. However, the role of Discoidin domain receptor 2 (DDR2), which is activated by collagen, in neurodegeneration remains poorly understood. This study uses immunoprecipitation followed by mass spectrometry on cytoplasmic and nuclear fractions from a neuronal cell model to show that Aβ42 exposure is associated with a compartment-specific reorganization of DDR2-associated protein complexes, characterized by increased nuclear representation. This reveals a unique nuclear DDR2 interactome under amyloidogenic conditions. By exploring this non-canonical, compartment-specific DDR2 signaling pathway, our results offer new insights into how receptor signaling networks may be altered in Alzheimer's disease pathology. Additionally, we identify DDR2-related nuclear interactions as potential sites of dysregulation in neurodegeneration.

Amyloid beta-Peptides↗
PubMed2006

Fine-tuning leukocyte responses: towards a chemokine 'interactome'.

The extended family of chemokines regulates the activation of leukocytes and coordinates their trafficking to sites of inflammation and during immune surveillance. The heptahelical-receptor-binding and function of chemokines is thought to be governed by their interaction with cell surface proteoglycans, oligomer formation, naturally occurring antagonists and proteolytic processing. Recent studies reveal that heterophilic interactions between chemokines can significantly modify their biological activities and through these we can gain initial insights into the structural basis underlying this novel regulatory mechanism. Here, we propose the concept of a functional 'interactome', constituted by a variety of heterophilic chemokine-chemokine interactions in particular microenvironments. This model could establish how signals conferred by various chemokines are integrated for the combinatorial control of leukocyte responses.

Animals↗
PubMed2026

DORSSAA: Drug-Target interactOmics Resource Based on Stability/Solubility Alteration Assay.

Advancements in high-throughput techniques such as Thermal Proteome Profiling and the high-throughput Proteome Integral Solubility Alteration assay have revolutionized our understanding of drug-protein interactions. Despite these innovations, the absence of an integrative platform for cross-study analysis of stability and solubility alteration data represents a significant bottleneck. To address this gap, we introduce Drug-target interactOmics Resource based on Stability/Solubility Alteration Assay (DORSSAA), an interactive and expandable web-based platform for the systematic analysis and visualization of proteome stability and solubility alteration assay datasets. Currently, DORSSAA features 1,135,985 records spanning 38 cell lines and organisms, 135 compounds, and 40,742 protein targets. Through its user-friendly interface, the resource supports comparative drug-protein interaction analysis and facilitates the discovery of actionable therapeutic targets. Through two case studies, methotrexate target profiling in A549 cells and combinatorial-therapy drug-target interactions in leukemia cell lines, we demonstrate DORSSAA's utility for identifying protein-drug interactions across diverse experimental contexts. This resource empowers researchers to accelerate drug discovery and enhance our understanding of protein behavior. Compared with data repositories and interaction databases, DORSSAA provides direct protein-level evidence of mechanisms of action with strict statistical control for each study. This enables more reliable identification of drug targets, off-target effects, and potential drug combinations.

Humans↗
PubMed2006

Unraveling androgen receptor interactomes by an array-based method: discovery of proto-oncoprotein c-Rel as a negative regulator of androgen receptor.

The androgen receptor (AR) plays a key role in the development and function of male reproductive organs. Using a high-throughput transcription factor-transcription factor (TF-TF) interaction array method, we captured the AR interactomes in androgen-responsive LNCaP cells. Several known and unknown partners of AR, including AP-2, Pax 3/5 (BSAP), c-Rel, RREB-1, LIII BP, and NPAS2 were identified. We investigated one unreported AR-associated transcription factor, the proto-oncoprotein c-Rel, in detail. C-Rel belongs to the NF-kB/Rel families and is persistently active in a number of diseases, including cancer. The presence of c-Rel transcript, protein, and its in vitro and in vivo association with AR was determined. Co-localization of c-Rel with AR both in cytoplasm and nucleus was confirmed by indirect immunofluorescence analysis. Chromatin immunoprecipitation data indicated that c-Rel, like AR, is a part of the nucleoprotein complex regulating the androgen-responsive prostate-specific antigen (PSA) promoter. Overexpression of c-Rel downregulated the promoter activity of both PSA and GRE4-TATA-Luc plasmids in LNCaP and COS cells. Analysis of AR and c-Rel protein levels indicated that the promoter downregulation was not due to reciprocal decrease in the amounts of AR or c-Rel. In summary, we have identified several new partners of AR by using the TF-TF array method and have provided the first evidence of a functional role for c-Rel in androgen-responsive human prostate cancer cells.

Base Sequence↗
PubMed2026

An Arabidopsis Protein-Flavonoid Interactome Identifies Peroxiredoxin A as a Candidate for Flavonoid Action in Chloroplasts.

The ability of phytochemicals to act as small molecule effectors of protein function is a largely overlooked dimension of plant biochemistry. This is particularly true for the ubiquitous flavonoids where, despite abundant examples of functional interactions with human proteins, biological activities in plants are primarily attributed to ROS scavenging. We used affinity capture to explore the protein interactome of the flavonoid glycoside, rutin, in Arabidopsis seedlings. Unexpectedly, the 397 high-confidence candidates included numerous proteins associated with chloroplasts, where flavonoids are present at exceedingly low levels. Intriguingly, several identified targets are conserved with known flavonoid-interacting proteins in mammals, where the bioavailability of flavonoids is similarly low. Using one of these, the Arabidopsis plastidial 2-cys peroxiredoxin A, as a test case, this study substantiated the potential of affinity proteomics for identifying novel protein targets of phytochemicals and suggests that flavonoids modulate protein function in plants to a larger extent than previously suspected.

Arabidopsis↗
PubMed2006

Analysis of the cGMP/cAMP interactome using a chemical proteomics approach in mammalian heart tissue validates sphingosine kinase type 1-interacting protein as a genuine and highly abundant AKAP.

The cyclic nucleotide monophosphates cAMP and cGMP play an essential role in many signaling pathways. To analyze which proteins do interact with these second messenger molecules, we developed a chemical proteomics approach using cAMP and cGMP immobilized onto agarose beads, via flexible linkers in the 2- and 8-position of the nucleotide. Optimization of the affinity pull-down procedures in lysates of HEK293 cells revealed that a large variety of proteins could be pulled down specifically. Identification of these proteins by mass spectrometry showed that many of these proteins were indeed genuine cAMP or cGMP binding proteins. However, additionally many of the pulled-down proteins were more abundant AMP/ADP/ATP, GMP/GDP/GTP, or general DNA/RNA binding proteins. Therefore, a sequential elution protocol was developed, eluting proteins from the beads using solutions containing ADP, GDP, cGMP, and/or cAMP, respectively. Using this protocol, we were able to sequentially and selectively elute ADP, GDP, and DNA binding proteins. The fraction left on the beads was further enriched, for cAMP/cGMP binding proteins. Transferring this protocol to the analysis of the cGMP/cAMP "interactome" in rat heart ventricular tissue enabled the specific pull-down of known cAMP/cGMP binding proteins such as cAMP and cGMP dependent protein kinases PKA and PKG, several phosphodiesterases and 6 AKAPs, that interact with PKA. Among the latter class of proteins was the highly abundant sphingosine kinase type1-interating protein (SKIP), recently proposed to be a potential AKAP. Further bioinformatics analysis endorses that SKIP is indeed a genuine PKA interacting protein, which is highly abundant in heart ventricular tissue.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Analysis of the human protein interactome and comparison with yeast, worm and fly interaction datasets.

We present the first analysis of the human proteome with regard to interactions between proteins. We also compare the human interactome with the available interaction datasets from yeast (Saccharomyces cerevisiae), worm (Caenorhabditis elegans) and fly (Drosophila melanogaster). Of >70,000 binary interactions, only 42 were common to human, worm and fly, and only 16 were common to all four datasets. An additional 36 interactions were common to fly and worm but were not observed in humans, although a coimmunoprecipitation assay showed that 9 of the interactions do occur in humans. A re-examination of the connectivity of essential genes in yeast and humans indicated that the available data do not support the presumption that the number of interaction partners can accurately predict whether a gene is essential. Finally, we found that proteins encoded by genes mutated in inherited genetic disorders are likely to interact with proteins known to cause similar disorders, suggesting the existence of disease subnetworks. The human interaction map constructed from our analysis should facilitate an integrative systems biology approach to elucidating the cellular networks that contribute to health and disease states.

Animals↗
PubMed2026

Comprehensive proximity proteomics expand the known interactome of the oncoprotein β-catenin.

The oncoprotein β-catenin has critical roles in cell adhesion and cell signalling. β-catenin affects human physiology and pathology through numerous interaction partners, of which many have been discovered by standard affinity purification-based proteomics. However, the interaction landscape of β-catenin remains incompletely understood, highlighting a need for new experimental approaches for the exploration of β-catenin biology. Proximity proteomics, which facilitate the discovery of molecules vicinal to proteins-of-interest by mass spectrometry, have recently emerged as a powerful complementary tool for the study of protein-protein interactions, but have not been applied to β-catenin so far. We investigated the interactome of β-catenin in model cell lines by proximity proteomics using expression constructs with the biotin ligases BioID and TurboID. Mass spectrometry analyses following biotin labelling identified numerous candidate interactors of β-catenin, including many that had not been observed in earlier studies using standard proteomics. Enrichment analyses suggested that proximity proteomics capture proteins associated with the known biological functions of β-catenin, including cell adhesion, Wnt/β-catenin signalling, and transcription regulation. The molecular tools and data generated in this study provide new insights into β-catenin biology and highlight potential new regulators of β-catenin function that warrant further exploration.

beta Catenin↗
PubMed2006

Disrupted in Schizophrenia 1 Interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia.

Disrupted in Schizophrenia 1 (DISC1) is a schizophrenia risk gene associated with cognitive deficits in both schizophrenics and the normal ageing population. In this study, we have generated a network of protein-protein interactions (PPIs) around DISC1. This has been achieved by utilising iterative yeast-two hybrid (Y2H) screens, combined with detailed pathway and functional analysis. This so-called 'DISC1 interactome' contains many novel PPIs and provides a molecular framework to explore the function of DISC1. The network implicates DISC1 in processes of cytoskeletal stability and organisation, intracellular transport and cell-cycle/division. In particular, DISC1 looks to have a PPI profile consistent with that of an essential synaptic protein, which fits well with the underlying molecular pathology observed at the synaptic level and the cognitive deficits seen behaviourally in schizophrenics. Utilising a similar approach with dysbindin (DTNBP1), a second schizophrenia risk gene, we show that dysbindin and DISC1 share common PPIs suggesting they may affect common biological processes and that the function of schizophrenia risk genes may converge.

Biological Transport↗
PubMed2004

Dynamic evolution of the adenine nucleotide translocase interactome during chemotherapy-induced apoptosis.

The mitochondrial permeability transition pore complex (PTPC) is involved in the control of the mitochondrial membrane permeabilization during apoptosis, necrosis and autophagy. Indeed, the adenine nucleotide translocator (ANT) and the voltage-dependent anion channel (VDAC), two major components of PTPC, are the targets of a variety of proapoptotic inducers. Using co-immunoprecipitation and proteomic analysis, we identified some of the interacting partners of ANT in several normal tissues and human cancer cell lines. During chemotherapy-induced apoptosis, some of these interactions were constant (e.g. ANT-VDAC), whereas others changed strongly concomitantly with the dissipation of the mitochondrial transmembrane potential and until nuclear degradation occurred (e.g. Bax, Bcl-2, subunits of the respiratory chain, a subunit of the phosphatase PP2A, phospholipase PLC beta 4 and IP3 receptor). In addition, a glutathione-S-transferase (GST) interacts with ANT in normal tissue, in colon carcinoma cells and in vitro. This interaction is lost during apoptosis induction, suggesting that GST behaves as an endogenous repressor of PTPC and ANT pore opening. Thus, ANT is connected to mitochondrial proteins as well as to proteins from other organelles such as the endoplasmic reticulum forming a dynamic polyprotein complex. Changes within this ANT interactome coordinate the lethal response of cells to apoptosis induction.

Animals↗
PubMed2006

Proteomics of acute myeloid leukaemia: Cytogenetic risk groups differ specifically in their proteome, interactome and post-translational protein modifications.

Acute myeloid leukaemia (AML) is characterized by specific cytogenetic aberrations that are strong determinants of prognostic outcome and therapeutic response. Because the pathological outcome of AML patients with cytogenetic abnormalities differs considerably, we hypothesized that their proteome may also differ specifically in their expression pattern, protein interaction pathways and post-translational modifications (PTM). We performed this study using 42 AML patients diagnosed for various cytogenetic abnormalities based on two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization time of flight mass spectrometry (MS) and MSMS tandem MS. We could identify significant differences in the proteome and PTM of peptides, later confirmed by other methods, between cytogenetic groups. The interactome analysis based on computational bioinformatics reveals major regulating networks: MAPK8 and MYC for complex aberrant karyotype, TP53 for t(8;21), TP53-MYC-PRKAC for 11q23 and JUN and MYC for Inv(16). Further, we analysed 42 MS spectra representative of hnRNPH1, calreticulin and hnRNPA2/B1 in a peak explorer, which reveals a cytogenetic-specific PTM of beta-O-linked N-acetyl glucosamine (O-GlcNAc) of hnRNPH1 in AML patients with 11q23 translocation, an acetylation of calreticulin in t(8;21) translocation and methylation of hnRNPA2/B1 in patients with translocations of t(8;21) and inv(16). This report may lead to a new thinking about AML pathogenesis, as differences at PTM level could be used to distinguish different subtypes of AML.

Cell Shape↗
PubMed2006

Free-energy distribution of binary protein-protein binding suggests cross-species interactome differences.

Major advances in large-scale yeast two-hybrid screening have provided a global view of binary protein-protein interactions across species as dissimilar as human, yeast, and bacteria. Remarkably, these analyses have revealed that all species studied have a degree distribution of protein-protein binding that is approximately scale-free (varies as a power law) even though their evolutionary divergence times differ by billions of years. The universal power law shows only the surface of the rich information harbored by these high-throughput data. We develop a detailed mathematical model of the protein-protein interaction network based on association free energy, the biochemical quantity that determines protein-protein interaction strength. This model reproduces the degree distribution of all of the large-scale yeast two-hybrid data sets available and allows us to extract the distribution of free energy, the likelihood that a pair of proteins of a given species will bind. We find that across-species interactomes have significant differences that reflect the strengths of the protein-protein interaction. Our results identify a global evolutionary shift: more evolved organisms have weaker binary protein-protein binding. This result is consistent with the evolution of increased protein unfoldedness and challenges the dogma that only specific protein-protein interactions can be biologically functional.

Animals↗
PubMed2001

A comprehensive two-hybrid analysis to explore the yeast protein interactome.

Protein-protein interactions play crucial roles in the execution of various biological functions. Accordingly, their comprehensive description would contribute considerably to the functional interpretation of fully sequenced genomes, which are flooded with novel genes of unpredictable functions. We previously developed a system to examine two-hybrid interactions in all possible combinations between the approximately 6,000 proteins of the budding yeast Saccharomyces cerevisiae. Here we have completed the comprehensive analysis using this system to identify 4,549 two-hybrid interactions among 3,278 proteins. Unexpectedly, these data do not largely overlap with those obtained by the other project [Uetz, P., et al. (2000) Nature (London) 403, 623-627] and hence have substantially expanded our knowledge on the protein interaction space or interactome of the yeast. Cumulative connection of these binary interactions generates a single huge network linking the vast majority of the proteins. Bioinformatics-aided selection of biologically relevant interactions highlights various intriguing subnetworks. They include, for instance, the one that had successfully foreseen the involvement of a novel protein in spindle pole body function as well as the one that may uncover a hitherto unidentified multiprotein complex potentially participating in the process of vesicular transport. Our data would thus significantly expand and improve the protein interaction map for the exploration of genome functions that eventually leads to thorough understanding of the cell as a molecular system.

Fungal Proteins↗
PubMed2006

Analysis of the ribosomal protein S19 interactome.

Ribosomal protein S19 (RPS19) is a 16-kDa protein found mainly as a component of the ribosomal 40 S subunit. Its mutations are responsible for Diamond Blackfan anemia, a congenital disease characterized by defective erythroid progenitor maturation. Dysregulation of RPS19 has therefore been implicated in this defective erythropoiesis, although the link between them is still unclear. Two not mutually exclusive hypotheses have been proposed: altered protein synthesis and loss of unknown functions not directly connected with the structural role of RPS19 in the ribosome. A role in rRNA processing has been surmised for the yeast ortholog, whereas the extracellular RPS19 dimer has a monocyte chemotactic activity. Three proteins are known to interact with RPS19: FGF2, complement component 5 receptor 1, and a nucleolar protein called RPS19-binding protein. We have used a yeast two-hybrid approach to identify a fourth protein: the serine-threonine kinase PIM1. The present study describes our use of proteomics strategies to look for proteins interacting with RPS19 to determine its functions. Proteins were isolated by affinity purification with a GST-RPS19 recombinant protein and identified using LCMS/MS analysis coupled to bioinformatics tools. We identified 159 proteins from the following Gene Ontology categories: NTPases (ATPases and GTPases; five proteins), hydrolases/helicases (19 proteins), isomerases (two proteins), kinases (three proteins), splicing factors (five proteins), structural constituents of ribosome (29 proteins), transcription factors (11 proteins), transferases (five proteins), transporters (nine proteins), DNA/RNA-binding protein species (53 proteins), other (one dehydrogenase protein, one ligase protein, one peptidase protein, one receptor protein, and one translation elongation factor), and 13 proteins of still unknown function. Proteomics results were validated by affinity purification and Western blotting. These interactions were further confirmed by co-immunoprecipitation using a monoclonal RPS19 antibody. Many interactors are nucleolar proteins and thus are expected to take part in the RPS19 interactome; however, some proteins suggest additional functional roles for RPS19.

Glutathione Transferase↗
PubMed2006

Hunting interactomes of a membrane protein: obtaining the largest set of voltage-dependent anion channel-interacting protein epitopes.

The identification of epitopes involved in protein-protein interactions is essential for understanding protein structure and function. Large scale efforts, although identifying the interactions, did not always yield these epitopes, could not confirm most of the known interactions, and seemed particularly unsuccessful for native intrinsic membrane proteins. We have developed a fluidics-based approach (non-steady-state kinetics) to obtain the broadest set of the epitopes interacting with a given target and applied it to a phage display methodology optimized for membrane proteins. Phages expressing a liver cDNA library were screened against a membrane protein (voltage-dependent anion channel) reconstituted into liposomes and captured on a chip surface. The controlled fluidics was obtained by a surface plasmon resonance (SPR) device that combined the advantages of working with minute reaction volumes and non-equilibrium conditions. We demonstrated selective enrichment of binders and could even select for different binding affinities by fractionation of the selected outputs at various elution times. With voltage-dependent anion channel as bait (a mitochondrial channel critical for cellular metabolism and apoptosis) we found at least 40% of its already reported ligands and independently confirmed 55 novel functional interactions, some of which fully blocked the channel. This highly efficient approach is generally applicable for any protein and could be automated and scaled up even without the use of a SPR device. The epitopes directly identified by this method are useful not only for unraveling interactomes but also for drug design and therapeutics.

Bacteriophages↗