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Laser flash melting experiments have rendered cryo-EM fast enough to observe the microsecond motions of proteins. The authors extend the observation window of this emerging technique tenfold, to hundreds of microseconds, by sealing cryo-EM samples in ultrathin liquid cells.

Guidance for optimizing lipid nanoparticle formulations is derived using sophisticated biophysical techniques.

Biopolymers can couple to membrane lipids and condense to prewet membranes. Here a range of membrane perturbations in reconstituted systems and cells show that the prewetting is sensitive to membrane composition and phase transitions and can drive interorganelle contact.

Geminin regulates DNA replication by binding CDT1 and preventing MCM helicase loading. Using a reconstituted system and structural modelling, the authors find geminin inhibits via steric clash with MCM, not by blocking the CDT1–MCM interface. Combined with CDK activity, it fully halts licensing.

Dysferlin is essential for plasma membrane repair, and mutations in this protein cause various muscle diseases. Here the authors report the structure of dysferlin, offering insights into its molecular mechanisms and how mutations impair its function.

Durable agonism of NPR1 achieved with a novel investigational monoclonal antibody could mirror the positive hemodynamic changes in blood pressure and heart failure identified in humans with lifelong exposure to NPR1 coding variants.

PUF proteins, conserved stem cell regulators, maintain germline stem cells with partner proteins in nematodes. Here, authors discover a complex of two FBF-2 PUF proteins and partner LST-1 that represses target mRNA via adjacent regulatory elements.

Nematode P granules are cytoplasmic RNA–protein biomolecule condensates central to germ cell development. Here the authors show that dimerization of the PGL-1 scaffolding protein is crucial to granule formation and mRNA repression, and that the WAGO-1 Argonaute protein is a cofactor in repressing PGL-1 bound mRNAs.

Formation of the mitotic checkpoint complex (MCC) is catalysed by a phosphorylation-dependent scaffold. This work provides structural details of how a tripartite Mad1:Bub1:Cdc20 complex presents Cdc20 to Mad2, triggering open-to-closed conversion of Mad2 to assemble the MCC.

Amyloid-like proteins are central to age-related diseases, such as Alzheimer’s and Parkinson’s. Here, the authors show that transcription errors can produce mutant proteins with enhanced amyloid- and prion-like properties in human cells.

Advances in deep learning are transforming protein design. Here, authors introduce a method using geometric transformers to predict protein sequences, resulting in highly thermostable and catalytically active enzymes with high success rates.

In a post-hoc analysis of circulating tumor DNA (ctDNA) features from patients with metastatic prostate cancer treated with [¹⁷⁷Lu]Lu–PSMA-617 or cabazitaxel in the randomized phase 2 TheraP trial, low ctDNA levels at baseline were predictive of clinical benefit from [¹⁷⁷Lu]Lu–PSMA-617, and PTEN or ATM alterations were identified as potential biomarkers of response.

Structural, biochemical and cellular studies reveal JMJD7 to be a Jumonji-C oxygenase that catalyzes (3S)-lysyl hydroxylation of the translation factor family of GTPases, DRG1 and DRG2.

Wendrich, Gallant and colleagues find that USP53 and USP54 are active deubiquitinases, with USP53 removing ubiquitin chains from substrate proteins in a chain-linkage-directed manner, and provide biochemical and structural insights into their mechanism, cellular substrates and disease implications.

Complexes that form between oppositely charged polyelectrolytes may be solid or liquid. Here, Perry et al.show that chirality in polypeptides can determine the state of those complexes based on a propensity for hydrogen-bond formation.

Severe COVID-19 is associated with epithelial and endothelial barrier dysfunction, however, the molecular pathways resulting in endothelial barrier dysfunction and vascular leakage are only sparsely understood. Here, Biering et al. show that SARS-CoV-2 spike protein is sufficient to induce barrier dysfunction and vascular leak. They show a role for integrins, TGF-beta, ECM remodeling enzymes, and glycosaminoglycans in this S-mediated barrier dysfunction.

Dynamin 2 is a large GTPase linked to several human diseases. Here, Gómez-Oca et al. investigate the functions of muscle dynamin 2 isoforms and provide insights into their differential implication in centronuclear myopathy pathogenesis and treatment.

TssA is an important component of the bacterial type VI secretion system (T6SS). Here, Dix et al. integrate structural, phylogenetic and functional analysis of the TssA subunits, providing new insights into their role in T6SS assembly and function.

RBR E3 ubiquitin ligases utilise a 2-step catalytic mechanism previously defined for only few of the RBR family members. Here, the authors examine the poorly studied RBRs HOIL-1 and RNF216 to define general principles of RBR catalysis and regulation and identify specific functional differences.

A surface-centric approach captures the physical and chemical determinants of molecular recognition, enabling the de novo design of protein interactions and of artificial proteins with function.

Controlling nanoscale interfaces is key for ensuring stable plasmonic and catalytic function yet remains difficult to achieve under operando conditions. Now it has been shown that transient Au–Cl adlayers function as redox-active Au(I) intermediates, modulating interfacial electrostatics. This modulation stabilizes gold nanogaps and directs ligand rebinding, thereby enabling reproducible regeneration of subnanometre architectures.

Sera from vaccinated individuals and some monoclonal antibodies show a modest reduction in neutralizing activity against the B.1.1.7 variant of SARS-CoV-2; but the E484K substitution leads to a considerable loss of neutralizing activity.

The lysosomal polyamine transporter ATP13A2 controls the cellular polyamine content, and impaired lysosomal polyamine export represents a lysosome-dependent cell death pathway that may be implicated in ATP13A2-associated neurodegeneration.

Chronic infection with SARS-CoV-2 leads to the emergence of viral variants that show reduced susceptibility to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma.

An integrated structural biology approach uncovers the structural complexity of the intrinsically disordered region (IDR) within the TRPV4 ion channel. Multiple stimulatory and inhibitory elements were identified within the IDR that modulate channel activity in a lipid-dependent manner.

A study of the evolution of the SARS-CoV-2 virus in England between September 2020 and June 2021 finds that interventions capable of containing previous variants were insufficient to stop the more transmissible Alpha and Delta variants.

Kuiper et al. and Prophet et al. implicate DNAJB6/HSP70 chaperone activities in the biogenesis of the nuclear pore complex permeability barrier and find that disease-linked nuclear envelope blebs are enriched in nucleoporin and chaperone condensates.

Using computational, spectroscopic and in vivo approaches, two short motifs in the N-terminal region of human α-synuclein are shown to be critical for toxic protein aggregation but also for membrane fusion.

Structural and biochemical analyses of human USP30 explain the basis of Lys6-linkage preference and regulation by PINK1 and Parkin, shedding light onto how USP30 can act as a brake on mitophagy.

Collagen lysyl hydroxylases promote cancer progression. Here the authors present the crystal structure of the lysyl hydroxylase domain of L230 from Acanthamoeba polyphaga mimivirus, which is of interest for LH inhibitor development, and show that ectopic expression of L230 in tumors promotes collagen cross-linking and metastasis.

Wyatt et al. explore glycaemic responses after a standardized meal and find that postprandial glycaemic dip is a predictor of hunger and subsequent energy intake.

SAMHD1 is a regulator of dNTP homeostasis and an HIV restriction factor. The authors use time-resolved cryo-EM to visualise dynamic conformational changes that drive the catalytic cycle and allosteric regulation of this multi-subunit enzyme.

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.

Post-international travel quarantine has been widely implemented to mitigate SARS-CoV-2 transmission, but the impacts of such policies are unclear. Here, the authors used linked genomic and contact tracing data to assess the impacts of a 14-day quarantine on return to England in summer 2020.

Genetic and testing data from England show that the SARS-CoV-2 variant of concern B.1.1.7 has a transmission advantage over other lineages.

SAMHD1 catalyses the hydrolysis of dNTPs into 2′-deoxynucleosides and triphosphate and is an important regulator of cellular dNTP homeostasis. Here, the authors provide insights into the catalytic mechanism of SAMHD1 by performing kinetic measurements and determining crystal structures of α-β-imido-dNTP inhibitor complexes, which reveal a bi-metallic iron-magnesium centre and catalytic hydroxyl molecule in the active site of the enzyme.

The Omicron variant evades vaccine-induced neutralization but also fails to form syncytia, shows reduced replication in human lung cells and preferentially uses a TMPRSS2-independent cell entry pathway, which may contribute to enhanced replication in cells of the upper airway. Altered fusion and cell entry characteristics are linked to distinct regions of the Omicron spike protein.

Carbon isotopic analysis reveals global biogeographic traits in shark trophic interactions, and sheds light on the diverse foraging behaviour of sharks.

EPAC1 is a cAMP-activated guanine nucleotide exchange factor (GEF) for Rap GTPases and a major transducer of cAMP signaling. Here, the authors show anionic membranes can activate EPAC1 independently of cAMP, increase its affinity for cAMP by two orders of magnitude, and synergize with cAMP to yield maximal GEF activity.

Single-stranded DNA annealing is driven by RAD52 open rings in association with RPA.

The proteasome complexes, composed of 20S core particles and one or two regulatory particles (proteasome activators), degrade most eukaryotic proteins. Here, the authors identify a sequence motif and resolve its interactions mediating the activation of the human 20S proteasome.

Vaccination efficiency in HIV infection is hampered by the low immunogenicity of HIV-1 Env glycoprotein (Env). Here authors optimise the neutralising antibody response to Env by stabilizing the Env trimers in the context of expressing them in a Newcastle Disease Virus-like particle and providing conditions that mimics replicating virus infection.

In this study the authors identify a possible link between the gene FAM222A and brain atrophy. The protein it encodes is found to accumulate in plaques seen in Alzheimer’s disease, and functional analysis suggests it interacts with amyloid-beta.

Cryo-EM analysis of the human CST–Polα/primase complex reveals a metazoan-specific mode of interaction between CST and DNA polymerase α that is proposed to function in telomeric recruitment of Polα/primase for C-strand maintenance.

In Saccharomyces cerevisiae, unchecked proliferation of Ty1 retrotransposons is controlled by the process of copy number control (CNC), which requires the p22/p18 protein, translated from an internal transcript within the Ty1 GAG gene. Here, the authors present the 2.8 Å crystal structure of a minimal p18 from Ty1-Gag that is able to restrict Ty1 transposition and identify two dimer interfaces in p18, whose roles were probed by mutagenesis both in vitro and in vivo. As p22/p18 contains only one of two conserved domains required for retroelement Gag assembly, they propose that p22/p18-Gag interactions block the Ty1 virus-like particle assembly pathway, resulting in defective particles incapable of supporting retrotransposition.

Metastatic castration-resistant prostate cancer is a highly aggressive disease, with a variable response to treatment. Here, the authors validate ctDNA fraction as a poor prognostic factor and develop a model to predict whether patients harbor sufficient ctDNA for informative blood-based genotyping.

Small CRISPR Cas9 proteins have potential in gene therapies but generally have poor editing efficiency or specificity and often recognize sub-optimal PAM sequences. Here the authors characterise four small nucleases and use protein engineering to create effective in vivo editors.

Magnetotactic bacteria must assemble magnetosomes into a linear chain that orients the cell along magnetic fields, yet how spiral bacteria with highly curved surfaces accomplish this is unclear. Here, MamY is shown to assemble into linear structures that serve as a scaffold for magnetosomes in magnetotactic spirilla.