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Understanding cellular processes requires a detailed knowledge of the underlying biochemistry. Here we showcase some of our recent articles in the areas of biochemistry, biophysics, structural biology and mass spectrometry that characterise biomolecules and their interactions in addition to methodology papers in these fields and related multidisciplinary work.
It is hard to correlate force, torque and localization information. The authors report Combined Optical and Magnetic BIomolecule TWEEZers, COMBI-Tweez, that integrates optical trapping, time-resolved electromagnetic tweezers, and fluorescence microscopy: they demonstrate visualisation of higher order structural motifs in DNA.
Here, authors use cryoEM, biochemistry and molecular dynamics simulations to delineate a functional cycle of RfaH, a universally conserved transcription factor that undergoes a fold-switch during recruitment to the transcribing RNA polymerase.
Here, the authors dissect the fuzzy interaction between the prokaryote transcription factor HigA2 and its DNA target and show that specific, transient interactions drive specificity despite HigA2 remaining mostly disordered.
Translation of RAPP (Arg-AlaPro-Pro) motifs induces ribosome stalling. Here, structures of RAPP-stalled ribosomes reveal that RAPP motifs short circuit the ribosomal peptidyltransferase activity to induce stalling.
Stalling of ribosomes by the nascent polypeptide chain is widely used to regulate gene expression. Here, Gersteuer et al determine cryo-EM structures of SecM-stalled ribosomes revealing the mechanism by which the SecM peptide arrests translation.
Nucleosome-protein complexes stick to the air-water interface and denature upon plunge freezing for cryoEM. Here, authors Chio and Palovcak et al. develop EM grids that protect such complexes and use these grids to study the ATP-dependent chromatin remodeler SNF2h.
Human protein DJ-1 displays neuroprotective properties. Here, the authors demonstrate that DJ-1 hydrolyzes cyclic 3-phosphoglyceric anhydride (cPGA), thereby protecting proteins from acylation by this highly reactive metabolite spontaneously forming in glycolysis.
Cystathionine beta-synthase is a conserved essential enzyme of one-carbon metabolism. Here, the authors show that the enzyme oligomerises to form filaments that undergo conformational and morphological changes in response to its activator S-adenosyl-L-methionine, the global methyl donor.
Traditional proteomics methods are complex and resource-intensive. Here, the authors develop One-Tip, a highly simplified approach that enables efficient, sensitive, and comprehensive analysis across various sample types, from blood plasma to single cells.
The study describes the molecular structure of the human histamine 2 receptor in active conformation and in complex with Gs heterotrimer, synthesized in a cell-free system and co-translationally inserted into preformed nanodiscs.
HPV’s E6 protein promotes cancer by degrading p53. This study reveals the cryoEM structure of HPV16 E6 in complex with E6AP and p53, highlighting their picomolar affinity and large protein-protein interaction interface.
Direct visualization of short-lived intermediates during active protein synthesis remains challenging. Here, the authors structurally capture transient translation intermediates to uncover temporary disome formation during ribosome collisions.
Direct modulation of protein by artificial catalysts as enzyme mimetics remains hindered by the lack of highly efficient catalytic centers. Here, the authors present the development of artificial protein modulators (APROMs) with protein phosphatase-like characteristics, catalytically reprogram the biological function of α-synuclein.
Discovery of new therapeutics has been hampered by the often-limiting resolution and throughput of cryo-EM. Here, the authors determine high-resolution cryo-EM structures of the CDK-activating kinase to establish a methodological framework for the use of cryo-EM in structure-based drug design.
Doa10/MARCHF6 is a conserved E3 ubiquitin ligase in the endoplasmic reticulum (ER) membrane in eukaryotes, but its molecular mechanism was unknown. The authors combine cryo-EM, computational and biochemical analyses to reveal how Doa10 recognizes its substrate proteins for ER-associated degradation.
Gene variants can affect folding and stability of the encoded protein. Here, the authors apply deep mutational scanning to provide genotype-phenotype information for 99% of the possible PRKN variants and reveal mechanistic details on how some variants cause loss-of-function and Parkinsons disease.
Do proteasomes catalyze peptide splicing? Here, the authors develop and apply a method to identify spliced peptides produced from entire proteins, confirm that proteasomes produce a sizeable variety of cis-spliced peptides with well-defined characteristics, and show that non-spliced and spliced peptides are concentrated in hotspots.
SAP05, a secreted effector of the obligate parasitic bacteria phytoplasma, bridges host SPL and GATA transcription factors (TFs) to the 26 S proteasome subunit RPN10 for ubiquitination-independent degradation. Here, the authors report the details on how SAP05 interacts with SPL5, GATA18 and RPN10.
The stoichiometry of Hrd1, an integral membrane E3 ubiquitin ligase is critical to maintaining proteostasis in the endoplasmic reticulum. Here, the authors establish a single-molecule counting approach coupled with a single-molecule in vitro ubiquitination system to determine the functional stoichiometry of Hrd1.
Ubiquitin E3 ligases are key to accessing ubiquitinated proteins, but only a few substrates have defined E3 ligases. Here, the authors reveal the mechanism of naturally occurring E3-independent ubiquitination and develop an E3-free enzymatic strategy for the versatile generation of ubiquitinated proteins.
The precise role of cochaperones and ATP hydrolysis in driving Hsp90’s chaperone cycle is largely unclear. Here, the authors use single-molecule FRET to show that several cochaperones are necessary to establish directionality in Hsp90’s conformational cycle.
Gram-negative bacteria rely on the Ton system for nutrient uptake. Here, authors uncover how the ExbD protein acts as a conformational switch and the function of peptidoglycan in order to energize this transport process across the outer membrane.
Radial spokes (RS) are crucial in coordinating ciliary motility. Here, authors use cryo-EM and cryo-ET to gain insight into mammalian RS divergence in ependymal cilia, RS assembly mechanism and the structure-function relationships of ciliary and flagellar axonemes.
Shigella enters human cells in a phagocytic vacuole and then escapes the vacuole to colonize the cytosol. Here, Chang and coworkers show that Shigella uses a bacterial effector to subvert host Rab proteins, microtubules and molecular motors to provide mechanical force to facilitate Shigella escape.
The Gabija system is a newly discovered bacterial immune system. Here, the authors report the EM structure of the Gabija complex at 3.6 Å. Here, the authors show that when invading phages depletes cellular NTP and dNTP, the nuclease activity of Gabija complex is activated and cleaves the circular DNA to prevent phage DNA replication.
Selective autophagy helps to degrade aggregated proteins accumulating in neurodegenerative diseases. Here, the authors show that NEMO, a ubiquitin binding protein previously linked to innate immune signaling, is recruited to misfolded proteins and promotes their autophagic clearance by forming condensates with the autophagy receptor p62.
LIM domain kinases are key regulators of cofilin and consequently actin severing. Here, the authors show that the LIMK PDZ domain is important for autoregulation using a conserved surface distal to the canonical PDZ-binding cleft.
Interferon stimulated gene 15 (ISG15) is a ubiquitin-like protein with critical roles in the innate immune response. Here, the authors present a Cryo-EM structure of ISG15 in complex with its E1 and E2 enzymes, providing insights into the specificity determinants of this pathway.
The cells of our bodies use chemical signals to talk with each other. Here the authors describe a class of signaling molecules called “capped peptides” that may mediate cell-cell communication. Unlike other peptides, capped peptides have unique chemical modifications which make them potentially more active and stable.
Intracellular bacteria use deubiquitinase effectors to avoid being targeted for autophagic clearance. The authors show that the Chlamydia-like bacterium Simkania negevensis encodes an unusually broad range of these enzymes, including members that specifically target linear and K6-linked ubiquitin chains.
Here the authors characterize DNAJB6 mutants found in LGMDD1 patients. They show that these mutants retain aggregation-prevention activity, but have impaired regulation of Hsp70 binding, uncontrollably recruiting Hsp70s, depleting the chaperone levels and disrupting proteostasis.
Cryptochromes are important components of biological clocks. Here, the authors uncover that a cryptochrome that enables synchronization of the reproduction of marine worms to the lunar cycle uses an inverse photo-oligomerization mechanism.
Inositol 1,4,5-trisphosphate receptors (IP3Rs) are intracellular Ca2+ channels that produce Ca2+ oscillations in response to GPCR and RTK activation. Here, Paknejad et al. resolve the conformational landscape of IP3Rs that gives rise to the biphasic dependence on Ca2+ for channel activity.
An integrated structural biology approach is utilized to elucidate the solution structure of the polypyrimidine-tract binding protein 1 (PTBP1/hnRNP I) complexed with an internal ribosome entry site (IRES) RNA fragment from encephalomyocarditis virus (EMCV).
Mapping protein turnover dynamics with subcellular precision is crucial for understanding cell physiology and pathology. Here, the authors leveraged APEX2-mediated proximity labeling to develop prox-SILAC methods to profile protein turnover rates in the mitochondria and endoplasmic reticulum.
Public proteomics data often lack essential metadata, limiting their potential. To address this, the authors developed lesSDRF, a tool to simplify the process of metadata annotation, thereby ensuring that data leave a lasting, impactful legacy well beyond their initial publication.
Histamine receptor H4R is implicated in chronic inflammatory diseases, such as asthma, arthritis, and atopic dermatitis. Here, the authors determined the first cryo-EM structure of the histamine H4 receptor, providing valuable structural insights for the design of drugs targeting H4R in chronic inflammatory diseases.
The most common protein modification in eukaryotes is N-terminal acetylation, but its functional impact has remained enigmatic. Here, the authors find that a key role for N-terminal acetylation is shielding proteins from ubiquitin ligase-mediated degradation, mediating motility and longevity.
Here, using cryo-FIB and cryo-ET, the authors delineate the architecture of native chromatin fibers and decipher the in situ nucleosomes structure, inspiring future chromatin research.
In this work, the authors report that Histidine residues play a critical role in modulating amyloid-like assembly and building active sites for Fmoc–F–F and Aβ aggregates. Aβ1-42 filaments were found to perform peroxidase-like activity to enhance oxidative stress, which might also be ascribed to the interaction mode of His and F-F.
Bcs1, a transmembrane AAA-ATPase, facilitates the translocation of folded ISP across the inner mitochondrial membrane. This study shows that the Bcs1 ATPase cycle conformational changes are highly concerted, unlike the canonical hand-over-hand mechanism.
Nano-environmental probes and advance imaging microscopy provide deep insight into protein phase separation and the interaction of condensates with membranes, revealing that wetting by condensates can modulate membrane lipid packing and hydration.
A key step of drug metabolism in the human body is the uptake into liver cells, which is mediated by transport proteins of the OATP family. Here, authors report cryo-EM structures of two human OATP proteins, providing insight into their function.
The AAA ATPase Pex1/Pex6 fuels the enzyme import across the peroxisomal membrane. Defects in either ATPase in humans result in severe disorders and early death. Here, the authors provide a detailed cryo-EM structures of the complex in the process of translocating an endogenous substate.
Here the authors describe principles for de novo designing single-chain immunoglobulin dimers with interfaces diverging from those seen in antibodies, showing enhanced stability and both robustness and modularity for harboring multiple functional loops.
Aminoacyl-tRNA synthetases translate the genetic code. These enzymes harbor signature catalytic motifs dating from their ancient ancestors. A natural variation of one of the stated motifs was discovered and linked to antibiotic hyper-resistance.
Most globular proteins are selected to fold into one unique structure. Schafer and Porter demonstrate that some proteins are selected to assume two stable folds; they leverage this information to predict two structures from one sequence.
Single-cell proteomics by Mass Spectrometry (scpMS) provides unparalleled insights into cellular mechanisms from a proteome-centric standpoint. Here, the authors leverage sensitivity-tailored data acquisition methods to profile cell state heterogeneity in cultured model systems.
Carboxysomes are bacterial proteinaceous organelle encapsulating enzymes and pathways to enhance carbon fixation. Here, authors engineer and determine cryoEM structure of minimal α-carboxysome shells to uncover the principle of shell assembly and encapsulation by CsoS2.
In this work, the authors report the utilization of nano-inhibito C3N nanodots to inhibit Aβ peptides aggregation and fibrils disassembly, and show how they induce a cognitive enhancement in treated AD mice.