The poly-l-proline type II (PPII) helix in recent years has emerged clearly as a structural class not only of fibrillar proteins (in collagen, PPII is a dominant conformation) but also of the folded ...and unfolded proteins. Although much less abundant in folded proteins than the α-helix and β-structure, the left-handed, extended PPII helix represents the only frequently occurring regular structure apart from these two structure classes. Natively unfolded proteins have a high content of the PPII helices identified by spectroscopic methods. Apart from the structural function, PPII is favorable for protein–protein and protein–nucleic acid interactions and plays a major role in signal transduction and protein complex assembly, as this structure is often found in binding sites, specifically binding sites of widely spread SH3 domains. PPII helices do not necessarily contain proline, but proline has high PPII propensity. Commonly occurring proline-rich regions, serving as recognition sites, are likely to have PPII structure. PPII helices are involved in transcription, cell motility, self-assembly, elasticity, and bacterial and viral pathogenesis, and has an important structural role in amyloidogenic proteins. However, PPII helices are not always assigned in experimentally solved structures, and they are rarely used in protein structure modeling. We aim to give an overview of this structural class and of the place it holds in our current understanding of protein structure and function. This review is subdivided into three main parts: the first part covers PPII helices in unfolded peptides and proteins, the second part includes studies of the PPII helices in folded proteins, and the third part discusses the functional role of the PPII.
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► The PPII helix is an extended, flexible left-handed helix without regular hydrogen bonds. ► PPII commonly occurs in folded proteins; it is abundant in unfolded proteins. ► PPII helices do not necessarily contain proline but proline has high PPII propensity. ► PPII has an important structural role and forms protein binding motifs. ► The PPII helix is a structure class comparable with the α-helix and β-structure.
: Combination antiretroviral therapy has dramatically changed the outcome of HIV infection, turning it from a death sentence to a manageable chronic disease. However, comorbidities accompanying HIV ...infection, such as metabolic and cardio-vascular diseases, as well as cognitive impairment, persist despite successful virus control by combination antiretroviral therapy and pose considerable challenges to clinical management of people living with HIV. These comorbidities involve a number of pathological processes affecting a variety of different tissues and cells, making it challenging to identify a common cause(s) that would link these different diseases to HIV infection. In this article, we will present evidence that impairment of cellular cholesterol metabolism may be a common factor driving pathogenesis of HIV-associated comorbidities. Potential implications for therapeutic approaches are discussed.
LASER IONIZATION MASS SPECTROMETRY AT 55: QUO VADIS? Azov, Vladimir A.; Mueller, Larissa; Makarov, Alexander A.
Mass spectrometry reviews,
January/February 2022, 2022-01-00, 20220101, Letnik:
41, Številka:
1
Journal Article
Recenzirano
Laser ionization mass spectrometry (LIMS) was one of the first practical methods developed for in situ analysis of the surfaces of solid samples. This review will encompass several aspects related to ...this analytical method. First, we will discuss the process of laser ionization, the influence of the laser type on its performance, and imaging capabilities of this method. In the second chapter, we will follow the historic development of LIMS instrumentation. After a brief overview of the first‐generation instruments developed in 1960–1990 years, we will discuss in detail more recent designs, which appeared during the last 2–3 decades. In the last part of our review, we will cover the recent applications of LIMS for surface analysis. These applications include various types of analyses of solid inorganic, organic, and heterogeneous samples, often in combination with depth profiling and imaging capability.
Hepatitis C virus (HCV) infection is accompanied by the induction of oxidative stress, mediated by several virus proteins, the most prominent being the nucleocapsid protein (HCV core). Here, using ...the truncated forms of HCV core, we have delineated several mechanisms by which it induces the oxidative stress. The N-terminal 36 amino acids of HCV core induced TGF\(\upbeta\)1-dependent expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases 1 and 4, both of which independently contributed to the production of reactive oxygen species (ROS). The same fragment also induced the expression of cyclo-oxygenase 2, which, however, made no input into ROS production. Amino acids 37-191 of HCV core up-regulated the transcription of a ROS generating enzyme cytochrome P450 2E1. Furthermore, the same fragment induced the expression of endoplasmic reticulum oxidoreductin 1\(\upalpha\). The latter triggered efflux of Ca2+ from ER to mitochondria via mitochondrial Ca2+ uniporter, leading to generation of superoxide anions, and possibly also H2O2. Suppression of any of these pathways in cells expressing the full-length core protein led to a partial inhibition of ROS production. Thus, HCV core causes oxidative stress via several independent pathways, each mediated by a distinct region of the protein.
Ground-based microwave radiometers are increasingly used in operational meteorology and nowcasting. These instruments continuously measure the spectra of downwelling atmospheric radiation in the ...range 20–60 GHz used for the retrieval of tropospheric temperature and water vapor profiles. Spectroscopic uncertainty is an important part of the retrieval error budget, as it leads to systematic bias. In this study, we analyze the difference between observed and simulated microwave spectra obtained from more than four years of microwave and radiosonde observations over Nizhny Novgorod (56.2° N, 44° E). We focus on zenith-measured and elevation-scanning data in clear-sky conditions. The simulated spectra are calculated by a radiative transfer model with the use of radiosonde profiles and different absorption models, corresponding to the latest spectroscopy research. In the case of zenith-measurements, we found a systematic bias (up to ~2 K) of simulated spectra at 51–54 GHz. The sign of bias depends on the absorption model. A thorough investigation of the error budget points to a spectroscopic nature of the observed differences. The dependence of the results on the elevation angle and absorption model can be explained by the basic properties of radiative transfer and by cloud contamination at elevation angles.
We demonstrate single-particle charge detection mass spectrometry on an Orbitrap for the analysis of megadalton biomolecular assemblies. We establish that the signal amplitudes of individual ions ...scale linearly with their charge, which can be used to resolve mixed ion populations, determine charge states and thus also determine the masses of individual ions. This enables the ultrasensitive analysis of heterogeneous protein assemblies including immunoglobulin oligomers, ribosomes, proteinaceous nanocontainers and genome-packed adeno-associated viruses.
Targeting aging mechanisms: pharmacological perspectives Moskalev, Alexey; Guvatova, Zulfiya; Lopes, Ines De Almeida ...
Trends in endocrinology and metabolism,
April 2022, 2022-04-00, 20220401, Letnik:
33, Številka:
4
Journal Article
Recenzirano
Geroprotectors slow down aging and promote healthy longevity in model animals. Although hundreds of compounds have been shown to extend the life of laboratory model organisms, clinical studies on ...potential geroprotectors are exceedingly rare, especially in healthy elders. This review aims to classify potential geroprotectors based on the mechanisms by which they influence aging. These pharmacological interventions can be classified into the following groups: those that prevent oxidation; proteostasis regulators; suppressors of genomic instability; epigenetic drugs; those that preserve mitochondrial function; inhibitors of aging-associated signaling pathways; hormetins; senolytics/senostatics; anti-inflammatory drugs; antifibrotic agents; neurotrophic factors; factors preventing the impairment of barrier function; immunomodulators; and prebiotics, metabiotics, and enterosorbents.
Geroprotectors or anti-aging drugs can slow down aging and promote a healthy lifespan.Pharmacological interventions in aging can be classified based on the mechanism of aging.Many geroprotectors may act in multiple pathways.Clinical studies are needed for approval of potential candidates as human geroprotectors.
Alzheimer's disease (AD) is the most common cause of dementia in the elderly, characterised by the accumulation of senile plaques and tau tangles, neurodegeneration, and neuroinflammation in the ...brain. The development of AD is a pathological cascade starting according to the amyloid hypothesis with the accumulation and aggregation of the β-amyloid peptide (Aβ), which induces hyperphosphorylation of tau and promotes the pro-inflammatory activation of microglia leading to synaptic loss and, ultimately, neuronal death. Modelling AD-related processes is important for both studying the molecular basis of the disease and the development of novel therapeutics. The replication of these processes is often achieved with the use of a purified Aβ peptide. However, Aβ preparations obtained from different sources can have strikingly different properties. This review aims to compare the structure and biological effects of Aβ oligomers and aggregates of a higher order: synthetic, recombinant, purified from cell culture, or extracted from brain tissue. The authors summarise the applicability of Aβ preparations for modelling Aβ aggregation, neurotoxicity, cytoskeleton damage, receptor toxicity in vitro and cerebral amyloidosis, synaptic plasticity disruption, and cognitive impairment in vivo and ex vivo. Further, the paper discusses the causes of the reported differences in the effect of Aβ obtained from the sources mentioned above. This review points to the importance of the source of Aβ for AD modelling and could help researchers to choose the optimal way to model the Aβ-induced abnormalities.
Beta amyloid peptide Aβ 1–42 (Aβ42) has a unique dual role in the human organism, as both the peptide with an important physiological function and one of the most toxic biological compounds provoking ...Alzheimer’s disease (AD). There are several known Aβ42 isoforms that we discuss here that are highly neurotoxic and lead to the early onset of AD. Aβ42 is an intrinsically disordered protein with no experimentally solved structure under physiological conditions. The objective of this research was to establish the appropriate molecular dynamics (MD) methodology and model a uniform set of structures for the Aβ42 isoforms that form the core of this study. For that purpose, force field selection and verification including convergence testing for MD simulations was made. Replica exchange MD and conventional MD modeling of several Aβ42 and Aβ16 isoforms that have neurotoxic and amyloidogenic effects impacting the severity of Alzheimer’s disease were carried out with the optimal force field and solvent parameters. A standardized ensemble of structures for the Aβ42 and Aβ16 isoforms covering 30–50% of the conformational ensembles extracted from the free energy minima was calculated from MD trajectories. The resulting data set of modeled structures includes Aβ42 wild type, isoD7, pS8, D7H, and H6R-Aβ42 and Aβ16 wild type, isoD7, pS8, D7H, and H6R-Aβ16. The representative structures are given in the Supporting Information; they are open for public access. In the study, we also evaluated the differences between the structures of Aβ42 isoforms and speculate on their possible relevance to the known functions. Utilizing several representative structures for a single disordered protein for docking, with their subsequent averaging by conformations, would markedly increase the reliability of docking results.
Native mass spectrometry continues to develop as a significant complement to traditional structural biology techniques. Within native mass spectrometry (MS), surface-induced dissociation (SID) has ...been shown to be a powerful activation method for the study of noncovalent complexes of biological significance. High-resolution mass spectrometers have become increasingly adapted to the analysis of high-mass ions and have demonstrated their importance in understanding how small mass changes can affect the overall structure of large biomolecular complexes. Herein we demonstrate the first adaptation of surface-induced dissociation in a modified high-mass-range, high-resolution Orbitrap mass spectrometer. The SID device was designed to be installed in the Q Exactive series of Orbitrap mass spectrometers with minimal disruption of standard functions. The performance of the SID-Orbitrap instrument has been demonstrated with several protein complex and ligand-bound protein complex systems ranging from 53 to 336 kDa. We also address the effect of ion source temperature on native protein–ligand complex ions as assessed by SID. Results are consistent with previous findings on quadrupole time-of-flight instruments and suggest that SID coupled to high-resolution MS is well-suited to provide information on the interface interactions within protein complexes and ligand-bound protein complexes.
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