The RING 2.0 web server for high quality residue interaction networks

open3noopenPiovesan, Damiano; Minervini, Giovanni; Tosatto, Silvio c.E.Piovesan, Damiano; Minervini, Giovanni; Tosatto, Silvi

The pVHL neglected functions, a tale of hypoxia-dependent and -independent regulations in cancer

The von Hippel-Lindau protein (pVHL) is a tumour suppressor mainly known for its role as master regulator of hypoxia-inducible factor (HIF) activity. Functional inactivation of pVHL is causative of the von Hippel-Lindau disease, an inherited predisposition to develop different cancers. Due to its impact on human health, pVHL has been widely studied in the last few decades. However, investigations mostly focus on its role in degrading HIFs, whereas alternative pVHL protein-protein interactions and functions are insistently surfacing in the literature. In this review, we analyse these almost neglected functions by dissecting specific conditions in which pVHL is proposed to have differential roles in promoting cancer. We reviewed its role in regulating phosphorylation as a number of works suggest pVHL to act as an inhibitor by either degrading or promoting downregulation of specific kinases. Further, we summarize hypoxia-dependent and -independent pVHL interactions with multiple protein partners and discuss their implications in tumorigenesis

Genotype-phenotype relations of the von Hippel-Lindau tumor suppressor inferred from a large-scale analysis of disease mutations and interactors

Familiar cancers represent a privileged point of view for studying the complex cellular events inducing tumor transformation. Von Hippel-Lindau syndrome, a familiar predisposition to develop cancer is a clear example. Here, we present our efforts to decipher the role of von Hippel-Lindau tumor suppressor protein (pVHL) in cancer insurgence. We collected high quality information about both pVHL mutations and interactors to investigate the association between patient phenotypes, mutated protein surface and impaired interactions. Our data suggest that different phenotypes correlate with localized perturbations of the pVHL structure, with specific cell functions associated to different protein surfaces. We propose five different pVHL interfaces to be selectively involved in modulating proteins regulating gene expression, protein homeostasis as well as to address extracellular matrix (ECM) and ciliogenesis associated functions. These data were used to drive molecular docking of pVHL with its interactors and guide Petri net simulations of the most promising alterations. We predict that disruption of pVHL association with certain interactors can trigger tumor transformation, inducing metabolism imbalance and ECM remodeling. Collectively taken, our findings provide novel insights into VHL-associated tumorigenesis. This highly integrated in silico approach may help elucidate novel treatment paradigms for VHL disease

Bluues server

Abstract Motivation: Electrostatic calculations are an important tool for deciphering many functional mechanisms in proteins. Generalized Born (GB) models offer a fast and convenient computational approximation over other implicit solvent-based electrostatic models. Here we present a novel GB-based web server, using the program Bluues, to calculate numerous electrostatic features including pKa-values and surface potentials. The output is organized allowing both experts and beginners to rapidly sift the data. A novel feature of the Bluues server is that it explicitly allows to find electrostatic differences between wild-type and mutant structures. Availability: The Bluues server, examples and extensive help files are available for non-commercial use at URL: http://protein.bio.unipd.it/bluues/. Contact: [email protected]

Arginine 107 of yeast ATP synthase subunit g mediates sensitivity of the mitochondrial permeability transition to phenylglyoxal

Modification with arginine-specific glyoxals modulates the permeability transition (PT) of rat liver mitochondria, with inhibitory or inducing effects that depend on the net charge of the adduct(s). Here, we show that phenylglyoxal (PGO) affects the PT in a species-specific manner (inhibition in mouse and yeast, induction in human and Drosophila mitochondria). Following the hypotheses (i) that the effects are mediated by conserved arginine(s) and (ii) that the PT is mediated by the F-ATP synthase, we have narrowed the search to 60 arginines. Most of these residues are located in subunits alpha, beta, gamma, epsilon, a, and c and were excluded because PGO modification did not significantly affect enzyme catalysis. On the other hand, yeast mitochondria lacking subunit g or bearing a subunit g R107A mutation were totally resistant to PT inhibition by PGO. Thus, the effect of PGO on the PT is specifically mediated by Arg-107, the only subunit g arginine that has been conserved across species. These findings are evidence that the PT is mediated by F-ATP synthase.Peer reviewe

RAPHAEL: recognition, periodicity and insertion assignment of solenoid protein structures.

Abstract Motivation: Repeat proteins form a distinct class of structures where folding is greatly simplified. Several classes have been defined, with solenoid repeats of periodicity between ca. 5 and 40 being the most challenging to detect. Such proteins evolve quickly and their periodicity may be rapidly hidden at sequence level. From a structural point of view, finding solenoids may be complicated by the presence of insertions or multiple domains. To the best of our knowledge, no automated methods are available to characterize solenoid repeats from structure. Results: Here we introduce RAPHAEL, a novel method for the detection of solenoids in protein structures. It reliably solves three problems of increasing difficulty: (1) recognition of solenoid domains, (2) determination of their periodicity and (3) assignment of insertions. RAPHAEL uses a geometric approach mimicking manual classification, producing several numeric parameters that are optimized for maximum performance. The resulting method is very accurate, with 89.5% of solenoid proteins and 97.2% of non-solenoid proteins correctly classified. RAPHAEL periodicities have a Spearman correlation coefficient of 0.877 against the manually established ones. A baseline algorithm for insertion detection in identified solenoids has a Q2 value of 79.8%, suggesting room for further improvement. RAPHAEL finds 1931 highly confident repeat structures not previously annotated as solenoids in the Protein Data Bank records. Availability: The RAPHAEL web server is available with additional data at http://protein.bio.unipd.it/raphael/ Contact: [email protected] Supplementary information: Supplementary data are available at Bioinformatics onlin

Massive non-natural proteins structure prediction using grid technologies

Background The number of natural proteins represents a small fraction of all the possible protein sequences and there is an enormous number of pr oteins never sampled by nature, the so called "never born proteins" (NBPs). A fundamental question in this regard is if the ensemble of natural proteins possesses peculiar chemical and physical properties or if it is just the product of contingency coupled to functional selection. A key feature of natural proteins is thei r ability to form a well defined three-dimensional structure. T hus, the structural study of NBPs can help to understand if natural protein sequences were selecte d for their peculiar properties or if they are just one of the possible stable and functional ensembles. Methods The structural characterization of a huge number of random proteins cannot be approached experimentally, thus the problem has been tackled using a computational approach. A large random protein sequences library (2 × 10 ^4 sequences) was generated, discarding amino acid sequences with significant simi larity to natural proteins, and the corresponding structures were predicted using Rosetta. Given th e highly computational demanding problem, Rosetta was ported in grid and a user friendly job submission environment was developed within the GENIUS Grid Portal. Protein structures generated were analysed in terms of net charge, secondary structure content, surface/volume ratio, hydrophobic core composition, etc. Results The vast majority of NBPs, according to the Rosetta mode l, are characterized by a compact three-dimensional structure with a high secondary structure content. Structure compactness and surface polarity are comparable to those of natural proteins, suggesting similar stability and solubility. Deviations are observed in α helix- β strands relative content and inydrophobic core composition, as NBPs appear to be richer in helical structure and aromatic amino acids with respect to natural proteins. Conclusion The results obtained suggest that the abil ity to form a compact, ordered and water-soluble structure is an intrinsic property of polypeptides. The tendency of random sequences to adopt α helical folds indicate that all-α proteins may have emerged ea rly in pre-biotic evolution. Further, the lower percentage of aromatic residu es observed in natural proteins has important evolutionary implications as far as tolerance to mutati ons is concerned

Protein sources alternative to meat: state of the art and involvement of fermentation

Meat represents an important protein source, even in developing countries, but its production is scarcely sustainable, and its excessive consumption poses health issues. An increasing number of Western consumers would replace, at least partially, meat with alternative protein sources. This review aims at: (i) depicting nutritional, functional, sensory traits, and critical issues of single-cell proteins (SCP), filamentous fungi, microalgae, vegetables (alone or mixed with milk), and insects and (ii) displaying how fermentation could improve their quality, to facilitate their use as food items/ingredients/supplements. Production of SCP (yeasts, filamentous fungi, microalgae) does not need arable land and potable water and can run continuously, also using wastes and byproducts. Some filamentous fungi are also consumed as edible mushrooms, and others are involved in the fermentation of traditional vegetable-based foods. Cereals, pseudocereals, and legumes may be combined to offer an almost complete amino acid profile. Fermentation of such vegetables, even in combination with milk-based products (e.g., tarhana), could increase nutrient concentrations, including essential amino acids, and improve sensory traits. Different insects could be used, as such or, to increase their acceptability, as ingredient of foods (e.g., pasta). However, insects as a protein source face with safety concerns, cultural constraints, and a lack of international regulatory framework.info:eu-repo/semantics/publishedVersio

Calmodulin Enhances Cryptochrome Binding to INAD in Drosophila Photoreceptors

Light is the main environmental stimulus that synchronizes the endogenous timekeeping systems in most terrestrial organisms. Drosophila cryptochrome (dCRY) is a light-responsive flavoprotein that detects changes in light intensity and wavelength around dawn and dusk. We have previously shown that dCRY acts through Inactivation No Afterpotential D (INAD) in a light-dependent manner on the Signalplex, a multiprotein complex that includes visual-signaling molecules, suggesting a role for dCRY in fly vision. Here, we predict and demonstrate a novel Ca2+-dependent interaction between dCRY and calmodulin (CaM). Through yeast two hybrid, coimmunoprecipitation (Co-IP), nuclear magnetic resonance (NMR) and calorimetric analyses we were able to identify and characterize a CaM binding motif in the dCRY C-terminus. Similarly, we also detailed the CaM binding site of the scaffold protein INAD and demonstrated that CaM bridges dCRY and INAD to form a ternary complex in vivo. Our results suggest a process whereby a rapid dCRY light response stimulates an interaction with INAD, which can be further consolidated by a novel mechanism regulated by CaM

Overall Survival Following Anastomotic Leakage After Surgery for Carcinoma of the Esophagus and Gastroesophageal Junction: A Systematic Review

The effect of anastomotic leakage, in patients who underwent surgery for carcinoma of the esophagus and gastroesophageal junction, on overall survival (OS) is a debated and controversial topic. The aim of this systematic review was to clarify the impact of anastomotic leakage on long-term survival of patients with esophageal cancer undergoing esophagectomy. A systematic literature review was carried out from 2000 to 2022. We chose articles reporting data from patients who underwent surgery for carcinoma of the esophagus and gastroesophageal junction. Data regarding 1-, 3- and 5-year OS were analyzed. Twenty studies met the inclusion criteria, yielding a total of 9,279 patients. Analyzing data from selected studies, anastomotic leakage was found to be associated with decreased OS in 5,456 cases while in the remaining 3,823 it had no impact on long term survival (p<0.05). However, this result did not emerge from the other studies considered in the systematic review. Anastomotic leakage is a severe postoperative complication, which seems to have an impact on overall survival. However, the topic remains debated and not supported by all case series included in this systematic review