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A C-terminal Processing Protease Implicated in Flagellin Turnover and Developmental Progression in a Bacterial Predator
Carboxy-terminal processing proteases (CTPs) are widely conserved bacterial proteases implicated in protein maturation, quality control, and stress responses, yet many family members functions remain unclear. Here, we characterise Bd0967, a previously unstudied CTP from the predatory bacterium Bdellovibrio bacteriovorus, and its role in flagellar function during predatory development. Crystal structures reveal a self-compartmentalised protease in which a PDZ domain forms a lid over a large...
Macrocycle screening against the C-terminal region of CHD4 uncovers its role as an interaction hub in the formation of the nucleosome remodeling and deacetylase complex
The Nucleosome Remodeling and Deacetylase complex (NuRD) plays a key role in regulating hemoglobin expression in adult erythroid cells. Selectively disrupting this complex potently induces the expression of fetal hemoglobin, a proven therapeutic strategy for treating beta-hemoglobinopathies such as sickle cell anemia. In these studies, we have used mRNA display to identify small macrocyclic peptides that inhibit the interaction between two core components of NuRD, the SANT-SLIDE domain of...
Mitochondria directly interact with the nuclear pore complex
Abstract Mitochondria regulate cellular processes through direct and indirect interactions with other organelles. A well-studied example has been contact with the endoplasmic reticulum at mitochondrial-associated endoplasmic reticulum membranes1, which control pathways including redox and calcium homeostasis2,3. Recent studies have also reported direct mitochondria–nuclear membrane contacts in cancer cells and yeast that promote pro-survival signalling4,5.
A genetic tool targeting brain GPR75
G-protein-coupled receptor 75 (GPR75) has emerged as an important mediator in diet-induced obesity (DIO) and a promising therapeutic target for anti-obesity drugs. However, the anatomical location of GPR75 in the brain remains unclear, hindering the understanding of GPR75 biology in DIO. Here, we generated a new GPR75-GFP-Ires-Cre knockin mouse strain, in which the Cre expression is driven by the endogenous GPR75 promoter and the GFP is fused with the C-terminal of the GPR75 protein.
NEK kinase TcRDK2 controls differentiation, host-cell infection, and remodeling of the translation initiation machinery in Trypanosoma cruzi
Trypanosoma cruzi, the etiologic agent of Chagas disease, alternates between replicative epimastigotes and amastigotes and non-dividing, mammal-infective metacyclic and bloodstream trypomastigotes. Protein phosphorylation is a major regulatory mechanism in trypanosomatids, whose kinomes reveal an expanded family of NIMA-related kinases (NEKs). Here, we investigated the role of T. cruzi RDK2 (Repressor of Differentiation Kinase 2), a conserved NEK that carries a C-terminal pleckstrin homology...
Copper transport to mitochondria by SLC25A3 contributes to skeletal myoblast differentiation and is required for survival of differentiated myotubes
Differentiation of skeletal muscle is associated with increased mitochondrial biogenesis and reliance of oxidative phosphorylation (OXPHOS). The terminal enzyme complex in the electron transport chain, cytochrome c oxidase (COX), requires copper for its assembly and activity, and copper delivery to mitochondria is essential for OXPHOS. However, when mitochondrial copper becomes essential during skeletal myoblast differentiation is not known.
Structural basis for chaperone-guided assembly of RNA-induced silencing complex
Abstract The RNA-induced silencing complex (RISC), comprising an Argonaute (AGO) protein and a small RNA, is the central effector in RNA silencing. Small RNAs are loaded onto AGO as bulky duplexes in an HSP70- and HSP90-dependent process1,2,3, but the molecular mechanism remains poorly understood. Here we identify the human AGO–HSP90–p23 complex, which captures AGO in an RNA-free state, termed the AGO maturation complex (AMC).
Diverse binding poses of agonistic neurotoxins on human Na<sub>v</sub>1.6
Abstract Voltage-gated sodium (Nav) channels are key targets of various venomous toxins. Deciphering the binding poses and mechanisms of action of representative toxins will help to dissect the functional mechanism of the channels and facilitate therapeutic development targeting Nav channels1,2. Here we present cryo-electron microscopy (cryo-EM) structures of distinct binding poses of three agonistic peptide toxins on the human Nav1.6–β1 channel complex.
Constitutive plasma membrane interaction of active Rho GEF Ect2 inhibits cortex contraction pulses
During cell division, multiple guanine nucleotide exchange factors (GEFs), including the mitotic regulator Ect2 and Lbc-type GEFs, regulate the dynamics of RhoA activity and actomyosin contractility. In interphase, Lbc-type GEFs are predominantly cytosolic and are transiently recruited to the plasma membrane via a Rho-dependent positive-feedback mechanism that generates stochastic pulses of Rho activity and cortical contractions. In contrast, during interphase, Ect2 is primarily sequestered...
Conserved structural features of RNA export pores spanning the double membrane of arterivirus and coronavirus replication organelles
Corona- and arteriviruses are distantly related positive-stranded RNA virus families within the order Nidovirales. Both transform intracellular membranes into double-membrane vesicles (DMVs) that serve as replication organelles. Newly made viral RNA presumably exits DMVs through double-membrane-spanning molecular pores formed by coronavirus nsp3-nsp4 and arterivirus nsp2-nsp3.