Trends in Biochemical Sciences

Neurohypophysial peptides are ancient and evolutionarily highly conserved neuropeptides that regulate many crucial physiological functions in vertebrates and invertebrates. The human neurohypophysial oxytocin/vasopressin (OT/VP) signaling system with its four receptors has become an attractive drug target for a variety of diseases, including cancer, pain, cardiovascular indications, and neurological disorders. Despite its promise, drug development faces hurdles, including signaling complexity, selectivity and off-target concerns, translational interspecies differences, and inefficient drug delivery...

Mitochondrial structure often determines the function of these highly dynamic, multifunctional, eukaryotic organelles, which are essential for maintaining cellular health. The dynamic nature of mitochondria is apparent in descriptions of different mitochondrial shapes [e.g., donuts, megamitochondria (MGs), and nanotunnels] and crista dynamics. This review explores the significance of dynamic alterations in mitochondrial morphology and regulators of mitochondrial and cristae shape. We focus on studies across tissue types and also describe new microscopy techniques for detecting mitochondrial morphologies both in vivo and in vitro that can improve understanding of mitochondrial structure...

Poly(UG) or 'pUG' dinucleotide repeats direct gene silencing in Caenorhabditis elegans by adopting an unusual quadruplex structure. Humans have thousands of pUG sequences and proteins that interact with them. The pUG fold reveals new aspects of gene regulation and RNA folding, highlighting how a simple sequence can encode a complex structure.

Plasma membranes utilize free energy to maintain highly asymmetric, non-equilibrium distributions of lipids and proteins between their two leaflets. In this review we discuss recent progress in quantitative research enabled by using compositionally controlled asymmetric model membranes. Both experimental and computational studies have shed light on the nuanced mechanisms that govern the structural and dynamic coupling between compositionally distinct bilayer leaflets. This coupling can increase the membrane bending rigidity and induce order - or lipid domains - across the membrane...

Optochemical tools have become potent instruments for understanding biological processes at the molecular level, and the past decade has witnessed their use in epigenetics and epitranscriptomics (also known as RNA epigenetics) for deciphering gene expression regulation. By using photoresponsive molecules such as photoswitches and photocages, researchers can achieve precise control over when and where specific events occur. Therefore, these are invaluable for studying both histone and nucleotide modifications and exploring disease-related mechanisms...

To fulfill their actual cellular role, individual microtubules become functionally specialized through a broad range of mechanisms. The 'search and capture' model posits that microtubule dynamics and functions are specified by cellular targets that they capture (i.e., a posteriori), independently of the microtubule-organizing center (MTOC) they emerge from. However, work in budding yeast indicates that MTOCs may impart a functional identity to the microtubules they nucleate, a priori. Key effectors in this process are microtubule plus-end tracking proteins (+TIPs), which track microtubule tips to regulate their dynamics and facilitate their targeted interactions...

Eukaryotic cells learn and adapt via unknown network architectures. Recent work demonstrated a circuit of two GTPases used by cells to overcome growth factor scarcity, encouraging our view that artificial and biological intelligence share strikingly similar design principles and that cells function as deep reinforcement learning (RL) agents in uncertain environments.

Louis Pasteur once famously said 'in the fields of observation chance favors only the prepared mind'. Much of chance is being in the right place at the right time. This is particularly true in the crowded molecular environment of the cell where being in the right place is often more important than timing. Although Brownian motion argues that enzymes will eventually bump into substrates, this probability is greatly enhanced if both molecules reside in the same subcellular compartment. However, activation of cell signaling enzymes often requires the transmission of chemical signals from extracellular stimuli to intracellular sites of action...

Two reports by Dhuri et al. and Oyaghire et al., respectively, show that, through installing chiral centers at the backbone of the artificial nucleic acid, peptide nucleic acid (PNA), enhanced miRNA targeting and genome modification can be achieved, with important implications in fighting cancers and β-thalassemia.

Recent advances in cryo-electron microscopy (Cryo-EM) have revolutionized our understanding of the complement C5a/C3a receptors that are crucial in inflammation. A recent report by Yadav et al. has elucidated the activation, ligand binding, selectivity, and signaling bias of these receptors, thereby enhancing structure-guided drug discovery. This paves the way for more effective anti-inflammatory therapies that target these receptors with unprecedented precision.

Histone lysine demethylases (KDMs) regulate eukaryotic gene transcription by catalysing the removal of methyl groups from histone proteins. These enzymes are intricately regulated by the kinase signalling system in response to internal and external stimuli. Here, we review the mechanisms by which kinase-mediated phosphorylation influence human histone KDM function. These include the changing of histone KDM subcellular localisation or chromatin binding, the altering of protein half-life, changes to histone KDM complex formation that result in histone demethylation, non-histone demethylation or demethylase-independent effects, and effects on histone KDM complex dissociation...

Eukaryotic transcription starts with the assembly of a preinitiation complex (PIC) on core promoters. Flanking this region is the +1 nucleosome, the first nucleosome downstream of the core promoter. While this nucleosome is rich in epigenetic marks and plays a key role in transcription regulation, how the +1 nucleosome interacts with the transcription machinery has been a long-standing question. Here, we summarize recent structural and functional studies of the +1 nucleosome in complex with the PIC. We specifically focus on how differently organized promoter-nucleosome templates affect the assembly of the PIC and PIC-Mediator on chromatin and result in distinct transcription initiation...

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Targeting translational factor proteins (TFPs) presents significant promise for the development of innovative antitubercular drugs. Previous insights from antibiotic binding mechanisms and recently solved 3D crystal structures of Mycobacterium tuberculosis (Mtb) elongation factor thermo unstable-GDP (EF-Tu-GDP), elongation factor thermo stable-EF-Tu (EF-Ts-EF-Tu), and elongation factor G-GDP (EF-G-GDP) have opened up new avenues for the design and development of potent antituberculosis (anti-TB) therapies.

Circadian clocks evolved in diverse organisms as an adaptation to the daily swings in ambient light and temperature that derive from Earth's rotation. These timing systems, based on intracellular molecular oscillations, synchronize organisms' behavior and physiology with the 24-h environmental rhythm. The cyanobacterial clock serves as a special model for understanding circadian rhythms because it can be fully reconstituted in vitro. This review summarizes recent advances that leverage new biochemical, biophysical, and mathematical approaches to shed light on the molecular mechanisms of cyanobacterial Kai proteins that support the clock, and their homologues in other bacteria...

Research retreats are elements of scientific graduate training programs. Although expected to provide strong educational value, some students are reluctant to attend. Here, we identify participation barriers and provide guidelines for retreat design that minimize obstacles and establish an inclusive environment to improve attendance and enrichment for all attendees.

At its most fundamental level, life is a collection of synchronized cellular processes driven by interactions among biomolecules. Proximity labeling has emerged as a powerful technique to capture these interactions in native settings, revealing previously unexplored elements of biology. This review highlights recent developments in proximity labeling, focusing on methods that push the fundamental technologies beyond the classic bait-prey paradigm, such as RNA-protein interactions, ligand/small-molecule-protein interactions, cell surface protein interactions, and subcellular protein trafficking...

A recent report by Chen et al. describes the discovery of RmNMT, a highly active and promiscuous tryptamine N-methyltransferase from the cane toad, Rhinella marina. N,N-dimethyltryptamine derivatives produced by this enzyme were then evaluated for their potential to serve as next-generation treatments for mental health disorders.

Membrane adenylyl cyclases (ACs) catalyze the conversion of ATP to the ubiquitous second messenger cAMP. As effector proteins of G protein-coupled receptors and other signaling pathways, ACs receive and amplify signals from the cell surface, translating them into biochemical reactions in the intracellular space and integrating different signaling pathways. Despite their importance in signal transduction and physiology, our knowledge about the structure, function, regulation, and molecular interactions of ACs remains relatively scarce...

The α-kinase eukaryotic elongation factor 2 kinase (eEF-2K) regulates translational elongation by phosphorylating its ribosome-associated substrate, the GTPase eEF-2. eEF-2K is activated by calmodulin (CaM) through a distinctive mechanism unlike that in other CaM-dependent kinases (CAMK). We describe recent structural insights into this unique activation process and examine the effects of specific regulatory signals on this mechanism. We also highlight key unanswered questions to guide future structure-function studies...