Structural Proteomics

The accumulation of manganese ions is crucial for scavenging reactive oxygen species and protecting the proteome of Deinococcus radiodurans (Dr). However, metal homeostasis still needs to be tightly regulated to avoid toxicity. DR2539, a dimeric transcription regulator, plays a key role in Dr manganese homeostasis. Despite comprising three well-conserved domains - a DNA-binding domain, a dimerisation domain, and an ancillary domain - the mechanisms underlying both, metal ion activation and DNA recognition remain elusive...

With growing recognition and acknowledgement of the genuine complexity of proteomes, we are finally entering the post-proteogenomic era. Routine assessment of proteomes as inferred correlates of gene sequences (i.e., canonical 'proteins') cannot provide the necessary critical analysis of systems-level biology that is needed to understand underlying molecular mechanisms and pathways or identify the most selective biomarkers and therapeutic targets. These critical requirements demand the analysis of proteomes at the level of proteoforms/protein species, the actual active molecular players...

MD2 pineapple ( Ananas comosus ) is the second most important tropical crop that preserves crassulacean acid metabolism (CAM), which has high water-use efficiency and is fast becoming the most consumed fresh fruit worldwide. Despite the significance of environmental efficiency and popularity, until very recently, its genome sequence has not been determined and a high-quality annotated proteome has not been available. Here, we have undertaken a pilot proteogenomic study, analyzing the proteome of MD2 pineapple leaves using liquid chromatography-mass spectrometry (LC-MS/MS), which validates 1781 predicted proteins in the annotated F153 (V3) genome...

INTRODUCTION: Alzheimer's disease (AD) is the predominant dementia globally, with heterogeneous presentation and penetrance of clinical symptoms, variable presence of mixed pathologies, potential disease subtypes, and numerous associated endophenotypes. Beyond the difficulty of designing treatments that address the core pathological characteristics of the disease, therapeutic development is challenged by the uncertainty of which endophenotypic areas and specific targets implicated by those endophenotypes to prioritize for further translational research...

The escalating crisis of antimicrobial resistance (AMR) underscores the urgent need for novel antimicrobials. One promising strategy is the exploration of structural diversity, as diverse structures can lead to diverse biological activities and mechanisms of action. This review delves into the role of structural diversity in antimicrobial discovery, highlighting its influence on factors such as target selectivity, binding affinity, pharmacokinetic properties, and the ability to overcome resistance mechanisms...

United States (US) Special Operations Forces (SOF) are frequently exposed to explosive blasts in training and combat, but the effects of repeated blast exposure (RBE) on SOF brain health are incompletely understood. Furthermore, there is no diagnostic test to detect brain injury from RBE. As a result, SOF personnel may experience cognitive, physical, and psychological symptoms for which the cause is never identified, and they may return to training or combat during a period of brain vulnerability. In 30 active-duty US SOF, we assessed the relationship between cumulative blast exposure and cognitive performance, psychological health, physical symptoms, blood proteomics, and neuroimaging measures (Connectome structural and diffusion MRI, 7 Tesla functional MRI, [11 C]PBR28 translocator protein [TSPO] positron emission tomography [PET]-MRI, and [18 F]MK6240 tau PET-MRI), adjusting for age, combat exposure, and blunt head trauma...

In the bloodstream of mammalian hosts, African trypanosomes face the challenge of protecting their invariant surface receptors from immune detection. This crucial role is fulfilled by a dense, glycosylated protein layer composed of variant surface glycoproteins (VSGs), which undergo antigenic variation and provide a physical barrier that shields the underlying invariant surface glycoproteins (ISGs). The protective shield's limited permeability comes at the cost of restricted access to the extracellular host environment, raising questions regarding the specific function of the ISG repertoire...

The sulfolipid sulfoquinovosyl diacylglycerol (SQDG), produced by plants, algae, and cyanobacteria, constitutes a major sulfur reserve in the biosphere. Microbial breakdown of SQDG is critical for the biological utilization of its sulfur. This commences through release of the parent sugar, sulfoquinovose (SQ), catalyzed by sulfoquinovosidases (SQases). These vanguard enzymes are encoded in gene clusters that code for diverse SQ catabolic pathways. To identify, visualize and isolate glycoside hydrolase CAZY-family 31 (GH31) SQases in complex biological environments, we introduce SQ cyclophellitol-aziridine activity-based probes (ABPs)...

UNLABELLED: Short sequences that mediate interactions with modular binding domains are ubiquitous throughout eukaryotic proteomes. Networks of Short Linear Motifs (SLiMs) and their corresponding binding domains orchestrate many cellular processes, and the low mutational barrier to evolving novel interactions provides a way for biological systems to rapidly sample selectable phenotypes. Mapping SLiM binding specificity and the rules that govern SLiM evolution is fundamental to uncovering the pathways regulated by these networks and developing the tools to manipulate them...

Host-microbe systems are evolutionary niches that produce coevolved biological interactions and are a key component of global health. However, these systems have historically been a difficult field of biological research due to their experimental intractability. Impactful advances in global health will be obtained by leveraging in silico screens to identify genes involved in mediating interspecific interactions. These predictions will progress our understanding of these systems and lay the groundwork for future in vitro and in vivo experiments and bioengineering projects...

Head and neck squamous cell carcinoma (HNSCC) is a major health concern due to its high mortality from poor treatment responses and locoregional tumor invasion into life sustaining structures in the head and neck. A deeper comprehension of HNSCC invasion mechanisms holds the potential to inform targeted therapies that may enhance patient survival. We previously reported that doublecortin like kinase 1 (DCLK1) regulates invasion of HNSCC cells. Here, we tested the hypothesis that DCLK1 regulates proteins within invadopodia to facilitate HNSCC invasion...

Identification of bacterial protein-protein interactions and predicting the structures of the complexes could aid in the understanding of pathogenicity mechanisms and developing treatments for infectious diseases. Here, we developed a deep learning-based pipeline that leverages residue-residue coevolution and protein structure prediction to systematically identify and structurally characterize protein-protein interactions at the proteome-wide scale. Using this pipeline, we searched through 78 million pairs of proteins across 19 human bacterial pathogens and identified 1923 confidently predicted complexes involving essential genes and 256 involving virulence factors...

Protein-protein interactions (PPIs) are ubiquitous in biology, yet a comprehensive structural characterization of the PPIs underlying biochemical processes is lacking. Although AlphaFold-Multimer (AF-M) has the potential to fill this knowledge gap, standard AF-M confidence metrics do not reliably separate relevant PPIs from an abundance of false positive predictions. To address this limitation, we used machine learning on well curated datasets to train a S tructure P rediction and O mics informed C lassifier called SPOC that shows excellent performance in separating true and false PPIs, including in proteome-wide screens...

With the development of large-scale intensive feeding, growth performance and animal welfare have attracted more and more attention. Exogenous probiotics can promote the growth performance of fish through improving intestinal microbiota; however, it remains unclear whether intestinal microbiota influence physiological biomarkers. Therefore, we performed metagenomic and metabolomic analysis to investigate the effects of a 90-day Lactiplantibacillus plantarum supplementation to a basal diet (1.0 × 108  CFU/g) on the growth performance, intestinal microbiota and their metabolites, and physiological biomarkers in Coilia nasus larvae...

Breast cancer, a highly formidable and diverse malignancy predominantly affecting women globally, poses a significant threat due to its intricate genetic variability, rendering it challenging to diagnose accurately. Various therapies such as immunotherapy, radiotherapy, and diverse chemotherapy approaches like drug repurposing and combination therapy are widely used depending on cancer subtype and metastasis severity. Our study revolves around an innovative drug discovery strategy targeting potential drug candidates specific to RTK signalling, a prominently targeted receptor class in cancer...

BACKGROUND: Bovine Genital Campylobacteriosis (BGC), a worldwide distributed venereal disease caused by Campylobacter fetus subsp. venerealis (Cfv), has a relevant negative economic impact in cattle herds. The control of BGC is hampered by the inexistence of globally available effective vaccines. The present in silico study aimed to develop a multi-epitope vaccine candidate against Cfv through reverse vaccinology. RESULTS: The analysis of Cfv strain NCTC 10354 proteome allowed the identification of 9 proteins suitable for vaccine development...

BACKGROUND: The mitochondria-associated endoplasmic reticulum membrane membranes (MAM), is the central hub for endoplasmic reticulum and mitochondria functional communicate. It plays a crucial role in hepatic lipid homeostasis. However, even though MAM has been acknowledged to be enriched in enzymes that contribute to lipid biosynthesis, no study has yet investigated the exact role of MAM on hepatic neutral lipid synthesis. OBJECTIVES: To address these gaps, this study investigated the systemic control mechanisms for MAM in neutral lipids synthesis by recruiting Seipin, focusing on the role of the Ip3r-Grp75-Vdac complex and their relevant Ca2+ signaling in this process...

Neurodegenerative disorders such as Parkinson's (PD) and Alzheimer's diseases (AD) are linked with the assembly and accumulation of proteins into structured scaffold called amyloids. These diseases pose significant challenges due to their complex and multifaceted nature. While the primary focus has been on endogenous amyloids, recent evidence suggests that bacterial amyloids may contribute to the development and exacerbation of such disorders. The gut-brain axis is emerging as a communication pathway between bacterial and human amyloids...

The diversity and dynamics of proteins play essential roles in maintaining the basic constructions and functions of cells. The abundance of functional proteins is regulated by the transcription and translation processes, while the alternative splicing enables the same gene to generate distinct protein isoforms of different lengths. Beyond the transcriptional and translational regulations, post-translational modifications (PTMs) are able to further expand the diversity and functional scope of proteins. PTMs have been shown to make significant changes in the surface charges, structures, activation states, and interactome of proteins...

The Fragile X messenger ribonucleoprotein (FMRP) is a complex, multi-domain protein involved in interactions with various macromolecules, including proteins and coding/non-coding RNAs. The three KH domains (KH0, KH1 and KH2) within FMRP are recognized for their roles in mRNA binding. In the context of Fragile X syndrome (FXS), over-and-above CGG triplet repeats expansion, three specific point mutations have been identified, each affecting one of the three KH domains (R138 QKH0, G266 EKH1, and I304N KH2) resulting in the expression of non-functional FMRP...