Surfaces as frameworks for intracellular organization.

A large fraction of soluble protein within the interior of living cells may reversibly associate with structural elements, including proteinaceous fibers and phospholipid membranes. In this opinion, we present theoretical and experimental evidence that many of these associations are due to nonspecific attraction between the protein and the surface of the fiber or membrane, and that such associations may lead to substantial changes in the association state of the adsorbed proteins, the biological function of the adsorbed proteins, and the distribution of these proteins between the many microenvironments existing within the cell.

Mapping Proximity Associations of Core Spindle Assembly Checkpoint Proteins.

The spindle assembly checkpoint (SAC) is critical for sensing defective microtubule-kinetochore attachments and tension across the kinetochore and functions to arrest cells in prometaphase to allow time to repair any errors before proceeding into anaphase. Dysregulation of the SAC leads to chromosome segregation errors that have been linked to human diseases like cancer. Although much has been learned about the composition of the SAC and the factors that regulate its activity, the proximity associations of core SAC components have not been explored in a systematic manner. Here, we have taken a BioID2-proximity-labeling proteomic approach to define the proximity protein environment for each of the five core SAC proteins BUB1, BUB3, BUBR1, MAD1L1, and MAD2L1 in mitotic-enriched populations of cells where the SAC is active. These five protein association maps were integrated to generate a SAC proximity protein network that contains multiple layers of information related to core SAC protein complexes, protein-protein interactions, and proximity associations. Our analysis validated many known SAC complexes and protein-protein interactions. Additionally, it uncovered new protein associations, including the ELYS-MAD1L1 interaction that we have validated, which lend insight into the functioning of core SAC proteins and highlight future areas of investigation to better understand the SAC.

Red Wine Dryness Perception Related to Physicochemistry.

The responsibility of condensed tannins in the astringency sensation is well-known, even though the physical mechanism is unclear. The aims of the study are to go deeper into the relationships between the tannin structure and red wine dryness as well as evaluate the influence of the wine matrix and tannin concentration on the interaction with proteins and dryness perception. Condensed tannins were extracted from two red wines (cv. Cabernet Sauvignon and Pinot Noir) and added back to them and to a model wine at 0.5 g/L, prior to chemical characterization of their composition by reversed-phase high-performance liquid chromatography as well as their viscosity. The physical consequences of interactions between mucin, poly-l-proline, saliva, and wines were evaluated by turbidimetry. Descriptive analysis and time-intensity evaluations of dryness were carried out by a trained panel on all wines and model solutions. The mean degree of polymerization of Cabernet Sauvignon wine with or without tannins added was higher than that of Pinot Noir wine conditions. The turbidity of saliva and poly-l-proline with tannins added to Cabernet Sauvignon was higher than of tannins added to Pinot Noir wine. Cabernet Sauvignon wines were perceived dryer than Pinot Noir by panelists, and the dryness intensity of Cabernet Sauvignon wine conditions last longer than that of Pinot Noir or model wine conditions. The dryness of red wines was related to larger tannins, higher tannin concentration, and a greater turbidity with saliva. The dryness was not affected by the addition of tannins into wine probably as a result of the aroma/taste suppression effects and the presence of other components.

18-kDa translocator protein association complexes in the brain: From structure to function.

The outer mitochondrial membrane 18-kDa translocator protein (TSPO) is highly conserved in organisms of different species and ubiquitously expressed throughout tissues, including the nervous system. In the healthy adult brain, TSPO expression levels are low and promptly modulated under different pathological conditions, such as cancer, inflammatory states, and neurological and psychiatric disorders. Not surprisingly, several endogenous and synthetic molecules capable of binding TSPO have been proposed as drugs or diagnostic tools for brain diseases. The most studied biochemical function of TSPO is cholesterol translocation into mitochondria, which in turn affects the synthesis of steroids in the periphery and neurosteroids in the brain. In the last 30 years, roles for TSPO have also been suggested in other cellular processes, such as heme synthesis, apoptosis, autophagy, calcium signalling and reactive oxygen species production. Herein, we provide an overview of TSPO associations with different proteins, focusing particular attention on their related functions. Furthermore, recent TSPO-targeted therapeutic interventions are explored and discussed as prospect for innovative treatments in mental and brain diseases.

The more the merrier: how homo-oligomerization alters the interactome and function of ribonucleotide reductase.

Stereotyped as a nexus of dNTP synthesis, the dual-subunit enzyme - ribonucleotide reductase (RNR) - is coming into view as a paradigm of oligomerization and moonlighting behavior. In the present issue of 'omics', we discuss what makes the larger subunit of this enzyme (RNR-α) so interesting, highlighting its emerging cellular interactome based on its unique oligomeric dynamism that dictates its compartment-specific occupations. Linking the history of the field with the multivariable nature of this exceedingly sophisticated enzyme, we further discuss implications of new data pertaining to DNA-damage response, S-phase checkpoints, and ultimately tumor suppression. We hereby hope to provide ideas for those interested in these fields and exemplify conceptual frameworks and tools that are useful to study RNR's broader roles in biology.

Clofarabine Commandeers the RNR-α-ZRANB3 Nuclear Signaling Axis.

Ribonucleotide reductase (RNR) is an essential enzyme in DNA biogenesis and a target of several chemotherapeutics. Here, we investigate how anti-leukemic drugs (e.g., clofarabine [ClF]) that target one of the two subunits of RNR, RNR-α, affect non-canonical RNR-α functions. We discovered that these clinically approved RNR-inhibiting dATP-analogs inhibit growth by also targeting ZRANB3-a recently identified DNA synthesis promoter and nuclear-localized interactor of RNR-α. Remarkably, in early time points following drug treatment, ZRANB3 targeting accounted for most of the drug-induced DNA synthesis suppression and multiple cell types featuring ZRANB3 knockout/knockdown were resistant to these drugs. In addition, ZRANB3 plays a major role in regulating tumor invasion and H-rasG12V-promoted transformation in a manner dependent on the recently discovered interactome of RNR-α involving select cytosolic-/nuclear-localized protein players. The H-rasG12V-promoted transformation-which we show requires ZRANB3-supported DNA synthesis-was efficiently suppressed by ClF. Such overlooked mechanisms of action of approved drugs and a previously unappreciated example of non-oncogene addiction, which is suppressed by RNR-α, may advance cancer interventions.

BMAA-protein interactions: A possible new mechanism of toxicity.

ß-N-methylamino-L-alanine (BMAA) has been shown to accumulate in organisms by associating with host proteins. It has been proposed that this association is the result of misincorporation of BMAA into the primary structure of proteins, specifically in the place of L-serine, and that this misincorporation causes protein misfolding resulting in the tangle formation typically associated with neurodegenerative diseases. However, more recent studies have questioned the validity of the BMAA misincorporation hypothesis. Furthermore, BMAA association with proteins in the absence of de novo protein synthesis has been demonstrated although the nature of these associations has not yet been characterized. We therefore sought to investigate the effects of these undescribed interactions on protein functioning, and to identify the site(s) of these interactions. We present data here to show that BMAA can inhibit the activity of certain enzymes, interfere with protein folding in the absence of de novo protein synthesis, and associate in vitro with commercial proteins to such an extent that it cannot be removed by protein precipitation or denaturation. Based on the observed effects of these interactions on protein functioning, we suggest that this might constitute an additional mechanism of toxicity that could help to explain the role of BMAA in the development of neurodegenerative diseases.

RWLPAP: Random Walk for lncRNA-protein Associations Prediction.

BACKGROUND: During recent years, a lot of experimental studies have shown that lncRNA-binding proteins play a key role in many biomedical processes. Therefore, it is important to predict the potential lncRNA-protein associations in biomedical researches. OBJECTIVE: To predict the associations between lncRNAs and proteins more reliably and more efficiently. METHOD: Considering the limitations of previous computational methods, we introduce a predictive model called Random Walk for lncRNA-Protein Associations Prediction (RWLPAP). It belongs to semi-supervised learning algorithms, and thus RWLPAP successfully avoids the difficulty of extracting negative data sets and features. RESULTS: By the leave-one-out cross validation, we compare RWLPAP with previous methods and conclude that RWLPAP has an AUC of 0.88, which is significantly higher than other three models. It suggests that RWLPAP is more reliable and effective in predicting the interactions between lncRNAs and proteins. CONCLUSION: In the case study, according to the rank of predictive scores, we can find that the scores of some lncRNA-protein associations are highly ranking by our method when is compared with other three methods. It indicates that our method is very effective and comprehensive. Therefore, we can expect that RWLPAP will be a useful bioinformatic tool in the future.

Non-Debye frustrated hydration steers biomolecular association: interfacial tension for the drug designer.

Many cellular functions involve the assembly of biomolecular complexes, a process mediated by water that gets displaced as subunits bind. This process affects water frustration, that is, the number of unmet hydrogen-bonding opportunities at the protein-water interface. By searching for least-frustrated aqueous interfaces, this study delineates the role of frustration in steering molecular assemblage. The search entails a trajectory sampling using a functional that measures the gradient of frustration and computing the resulting non-Debye electrostatics within relaxation times for coupled protein-water systems. The minimal frustration principle is validated against spectroscopic measurements of frustration-dependent dielectric relaxation, affinity scanning of protein-protein interfaces, and NMR-inferred association propensities of protein-complex intermediates. The methods are applied to drug design, revealing the targetable nature of the aqueous interface.