Search

The bacterial AAA+ ClpX unfolds substrates using the energy from ATP hydrolysis and delivers them to the associated protease ClpP. A loop with an aromatic-hydrophobic motif protrudes into the central pore of the ClpX hexamer and was known to be important for activity. Now mutational analysis using covalently linked subunits provides evidence that this loop actually grips the substrate and undergoes conformational changes to drive its translocation and unfolding.

The advantage of living in cities compared with rural areas with respect to height and BMI in children and adolescents has generally become smaller globally from 1990 to 2020, except in sub-Saharan Africa.

A data mining and machine learning approach for improving surveillance reveals clinically relevant antimicrobial resistance profiles across chicken farms, abattoirs and environments in three provinces in China.

Cholera continues to cause significant mortality in endemic regions such as Bangladesh where diverse lineages circulate. Here, the authors investigate genomic features that are associated with linage transmission dynamics and disease severity using machine learning, genome-scale metabolic modelling, and 3D structural analysis.

The heterogeneity of androgen receptor (AR) gene alterations across metastases in prostate cancer remains unresolved. Here, the authors characterise AR genomic complexity across spatially separated lethal metastases from 10 prostate cancer patients and investigate how AR alterations evolve.

Bacteria in the same environment can share genetic material but the extent to which this influences development of antimicrobial resistance is unclear. Here, the authors investigate the evidence for co-evolution of antimicrobial resistance in bacteria found coexisting in animals and the environment in chicken farms and slaughterhouses in China.

To survive and evade host responses, malaria parasites export several hundred proteins into the host cell on infection. A feature of these proteins is a conserved, pentameric motif that is cleaved by an unknown protease before export. This is one of two independent studies revealing the identity of the protease as plasmepsin V, an aspartic acid protease located in the endoplasmic reticulum. This enzyme is essential for parasite viability and is an attractive candidate for drug development.

The translocation channel of ClpXP, which must open for degradation, is closed by an axial pore-2 loop when recognizing the ssrA degron. Here the authors show that the channel is also closed in the absence of substrate in cryo-EM structures and find that mutational destabilization of the closed-channel conformation changes substrate specificity.

Analysis of HbA1c and FPG levels across 117 population-based studies demonstrates regional variation in prevalence of previously undiagnosed screen-detected diabetes using one or both measures and suggests that use of elevated FPG alone could underestimate diabetes prevalence in low- and middle-income countries.

An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

From 1980 to 2018, the levels of total and non-high-density lipoprotein cholesterol increased in low- and middle-income countries, especially in east and southeast Asia, and decreased in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe.

Vaccination is effective in protecting from COVID-19. Here the authors report immune responses and breakthrough infections in twice-vaccinated patients receiving anti-TNF treatments for inflammatory bowel disease, and find dampened vaccine responses that implicate the need of adapted vaccination schedules for these patients.

A diverse, multidisciplinary panel of 386 experts in COVID-19 response from 112 countries provides health and social policy actions to address inadequacies in the pandemic response and help to bring this public health threat to an end.

It is found that carbon export fluxes to the deep ocean from a highly productive, naturally iron-fertilized region of the sub-Antarctic Southern Ocean are two to three times larger than the carbon export fluxes from an adjacent high-nutrient low-chlorophyll area not fertilized by iron. These findings support the hypothesis that increased iron supply to the glacial sub-Antarctic may have directly enhanced carbon export to the deep ocean.

In this study, Aggarwal and colleagues perform prospective sequencing of SARS-CoV-2 isolates derived from asymptomatic student screening and symptomatic testing of students and staff at the University of Cambridge. They identify important factors that contributed to within university transmission and onward spread into the wider community.

In this largest whole-exome sequencing study of epilepsies to date, the Epi25 Collaborative identified extremely rare variants that confer risk for diverse epilepsy subtypes, highlighting roles in synaptic transmission and neuronal excitability.

Cryo-EM structures of the AAA+ ClpAP•ClpS protease-adaptor complex show degron-like ClpS binding, coordinated by pore-1 loops from either the D1 or the D1 and D2 rings of ClpA. D1-pore-2-loop activity is critical for ClpS-assisted degradation.

Contrary to the view that urbanization is a major driver of the global rise in obesity, the global increase in body-mass index is shown to be mostly due to increases in the body-mass indexes of rural populations.

Genome-wide association meta-analyses identify 26 risk loci for epilepsy, including 19 loci specific to genetic generalized epilepsy. Prioritized candidate genes implicate synaptic processes and overlap with targets of antiseizure medications.

Colonizing enteric bacteria are shown to inhibit the antimicrobial process of host cell apoptosis through the action of NleB1, a type III secretion system effector with N-acetylglucosamine transferase activity, which can bind and modify eukaryotic death-domain-containing proteins.

The construction of ClpX hexamers containing variable numbers and configurations of wild-type and grip-defective pore loops supports a model of concurrent loop movement that ensures substrate unfolding and translocation.

A single-molecule optical-trapping approach is used to examine protein unfolding and translocation by double-ring AAA+ machine ClpA. Although ClpA can unfold some substrates faster than ClpX can, it translocates the unfolded polypeptide more slowly.

A biochemical study reveals the AAA+ protein unfoldase ClpX functions as a closed ring and identifies regions required for intersubunit coupling during the ATPase cycle. These findings provide important insights on the ClpX mechanism that may be extended to other AAA+ proteins.

By examining Latin American individuals of mixed European, Native American and African ancestry, Adhikari et al. identify novel loci influencing various features of facial and scalp hair. The study also provides experimental evidence that one of the implicated genes (PRSS53) is expressed in the hair follicle and that the top associated variant alters processing of this enzyme.

The hexameric ClpX AAA+ ATPase requires subunit asymmetry and switching between nucleotide-loadable and nucleotide-unloadable conformations for cooperative ATP hydrolysis and efficient substrate binding, unfolding and degradation.

Passionate biochemist with a love for enzymes.

Zhang et al. show that the poly(GA) proteins produced in patients with C9ORF72 repeat expansions cause neurodegeneration and behavioral abnormalities when expressed in mice. The emergence of these phenotypes requires poly(GA) aggregation, and poly(GA) inclusions sequester HR23 proteins involved in proteasomal degradation, as well as proteins involved in nucleocytoplasmic transport.

Despite the identification of genetic risk loci for late-onset Alzheimer’s disease (LOAD), the genetic architecture and prediction remains unclear. Here, the authors use genetic risk scores for prediction of LOAD across three datasets and show evidence suggesting oligogenic variant architecture for this disease.

Cortical thickness is asymmetric, and cortical thinning occurs with age and in disease. Here the authors investigate if both cortices thin at the same rate or if the thicker hemisphere declines faster in aging and in Alzheimer’s disease.

Identification and characterization, using a comprehensive embryonic phenotyping pipeline, of 410 lethal alleles during the generation of the first 1,751 of 5,000 unique gene knockouts produced by the International Mouse Phenotyping Consortium.