Biochemical Society Transactions

Sister chromatid segregation is the final irreversible step of mitosis. It is initiated by a complex regulatory system that ultimately triggers the timely activation of a conserved cysteine protease named separase. Separase cleaves the cohesin protein ring that links the sister chromatids and thus facilitates their separation and segregation to the opposite poles of the dividing cell. Due to the irreversible nature of this process, separase activity is tightly controlled in all eukaryotic cells. In this mini-review, we summarize the latest structural and functional findings on the regulation of separase, with an emphasis on the regulation of the human enzyme by two inhibitors, the universal inhibitor securin and the vertebrate-specific inhibitor CDK1-cyclin B...

Life came to depend on iron as a cofactor for many essential enzymatic reactions. However, once the atmosphere was oxygenated, iron became both scarce and toxic. Therefore, complex mechanisms have evolved to scavenge iron from an environment in which it is poorly bioavailable, and to tightly regulate intracellular iron contents. In bacteria, this is typically accomplished with the help of one key regulator, an iron-sensing transcription factor. While Gram-negative bacteria and Gram-positive species with low guanine-cytosine (GC) content generally use Fur (ferric uptake regulator) proteins to regulate iron homeostasis, Gram-positive species with high GC content use the functional homolog IdeR (iron-dependent regulator)...

From a physical perspective, morphogenesis of tissues results from interplay between their material properties and the mechanical forces exerted on them. The importance of mechanical forces in influencing cell behaviour is widely recognised, whereas the importance of tissue material properties in vivo, like stiffness, has only begun to receive attention in recent years. In this mini-review, we highlight key themes and concepts that have emerged related to how tissue stiffness, a fundamental material property, guides various morphogenetic processes in living organisms...

The ability of cells to divide, migrate, relay signals, sense mechanical stimuli, and respond to stress all rely on nanoscale invaginations of the plasma membrane known as caveolae. The caveolins, a family of monotopic membrane proteins, form the inner layer of the caveolar coat. Caveolins have long been implicated in the generation of membrane curvature, in addition to serving as scaffolds for signaling proteins. Until recently, however, the molecular architecture of caveolins was unknown, making it impossible to understand how they operate at a mechanistic level...

microRNAs (miRs) have been reported over the decades as important regulators in bone development and bone regeneration. They play important roles in maintaining the stem cell signature as well as regulating stem cell fate decisions. Thus, delivering miRs and miR inhibitors to the defect site is a potential treatment towards craniofacial bone defects. However, there are challenges in translation of basic research to clinics, including the efficiency, specificity, and efficacy of miR manipulation methods and the safety of miR delivery systems...

Many membrane proteins including ion channels and ion transporters are regulated by membrane phospholipids such as phosphoinositides in cell membranes and organelles. Voltage-sensing phosphatase, VSP, is a voltage-sensitive phosphoinositide phosphatase which dephosphorylates PI(4,5)P2 into PI(4)P. VSP rapidly reduces the level of PI(4,5)P2 upon membrane depolarization, thus serving as a useful tool to quantitatively study phosphoinositide-regulation of ion channels and ion transporters using a cellular electrophysiology system...

Landmark genome-wide association studies (GWAS) identified that mutations in autophagy genes correlated with inflammatory bowel disease (IBD), a heterogenous disease characterised by prolonged inflammation of the gastrointestinal tract, that can reduce a person's quality of life. Autophagy, the delivery of intracellular components to the lysosome for degradation, is a critical cellular housekeeping process that removes damaged proteins and turns over organelles, recycling their amino acids and other constituents to supply cells with energy and necessary building blocks...

Cancer is a significant cause of death, precluding increasing life expectancy worldwide. That is a multifactorial disease initiated by intrinsic or extrinsic factors that induce cell differentiation into cancer cells. However, cancer development, progression, and metastasis are not controlled only by cancer cells. The entire environment around these cells, named tumor microenvironment (TME), influences tumor development and spread. The tumor microenvironment is formed by cancer cells and heterogenous nonmalignant cells integrated with a complex extracellular matrix...

In our human society, would you not want to know if your neighbor suddenly passed away? Tissues and cells are not that different. Cell death is an inevitable part of tissue homeostasis and comes in different flavors that can either be a consequence of an injury or a regulated phenomenon (such as programed cell death). Historically, cell death was viewed as a way to discard cells, without functional consequences. Today, this view has evolved and recognizes an extra layer of complexity: dying cells can provide physical or chemical signals to notify their neighbors...

G protein-coupled receptors (GPCRs) are key modulators of cell signaling. Multiple GPCRs are present in the heart where they regulate cardiac homeostasis including processes such as myocyte contraction, heart rate and coronary blood flow. GPCRs are pharmacological targets for several cardiovascular disorders including heart failure (HF) such as beta-adrenergic receptor (βAR) blockers and angiotensin II receptor (AT1R) antagonists. The activity of GPCRs are finely regulated by GPCR kinases (GRKs), which phosphorylate agonist-occupied receptors and start the process of desensitization...

The accumulation of aggregated α-synuclein in susceptible neurons in the brain, together with robust activation of nearby myeloid cells, are pathological hallmarks of Parkinson's disease (PD). While microglia represent the dominant type of myeloid cell in the brain, recent genetic and whole-transcriptomic studies have implicated another type of myeloid cell, bone-marrow derived monocytes, in disease risk and progression. Monocytes in circulation harbor high concentrations of the PD-linked enzyme leucine-rich repeat kinase 2 (LRRK2) and respond to both intracellular and extracellular aggregated α-synuclein with a variety of strong pro-inflammatory responses...

Barbeau's seesaw hypothesis of dopamine-acetylcholine balance has predominated movement disorders literature for years. Both the simplicity of the explanation and the matching efficacy of anticholinergic treatment in movement disorders seem to support this hypothesis. However, evidence from translational and clinical studies in movement disorders indicates that many features of this simple balance are lost, broken, or absent from movement disorders models or in imaging studies of patients with these disorders...

Ageing is a conserved and unavoidable biological process characterized by progressive decline of physiological functions with time. Despite constituting the greatest risk factor for most human diseases, little is known about the molecular mechanisms driving the ageing process. More than 170 chemical RNA modifications, also known as the epitranscriptome, decorate eukaryotic coding and non-coding RNAs and have emerged as novel regulators of RNA metabolism, modulating RNA stability, translation, splicing or non-coding RNA processing...

Arginine methylation is a ubiquitous and relatively stable post-translational modification (PTM) that occurs in three types: monomethylarginine (MMA), asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). Methylarginine marks are catalyzed by members of the protein arginine methyltransferases (PRMTs) family of enzymes. Substrates for arginine methylation are found in most cellular compartments, with RNA-binding proteins forming the majority of PRMT targets. Arginine methylation often occurs in intrinsically disordered regions of proteins, which impacts biological processes like protein-protein interactions and phase separation, to modulate gene transcription, mRNA splicing and signal transduction...

Mitochondrial calcium (Ca2+) signaling has long been known to regulate diverse cellular functions, ranging from ATP production via oxidative phosphorylation, to cytoplasmic Ca2+ signaling to apoptosis. Central to mitochondrial Ca2+ signaling is the mitochondrial Ca2+ uniporter complex (MCUC) which enables Ca2+ flux from the cytosol into the mitochondrial matrix. Several pivotal discoveries over the past 15 years have clarified the identity of the proteins comprising MCUC. Here, we provide an overview of the literature on mitochondrial Ca2+ biology and highlight recent findings on the high-resolution structure, dynamic regulation, and new functions of MCUC, with an emphasis on publications from the last five years...

Both fetal and tumor tissue microenvironments display immunosuppressive features characterized by the presence of specific immunomodulatory stromal and immune cell populations. Recently, we discovered shared microenvironments between hepatocellular carcinoma (HCC) and fetal tissues and described this phenomenon as an oncofetal ecosystem. This ecosystem includes fetal-like immune (macrophage) and stromal (endothelial) cells within the tumor microenvironment (TME). This discovery highlights reciprocal interactions between fetal-like macrophages and T cells which result in the orchestration of an immunosuppressive TME...

A healthy brain is protected by the blood-brain barrier (BBB), which is formed by the endothelial cells that line brain capillaries. The BBB plays an extremely important role in supporting normal neuronal function by maintaining the homeostasis of the brain microenvironment and restricting pathogen and toxin entry to the brain. Dysfunction of this highly complex and regulated structure can be life threatening. BBB dysfunction is implicated in many neurological diseases such as stroke, Alzheimer's disease, multiple sclerosis, and brain infections...

Point mutations in leucine-rich repeat kinase 2 (LRRK2) which cause Parkinson's disease increase its kinase activity, and a subset of Rab GTPases have been identified as endogenous LRRK2 kinase substrates. Their phosphorylation correlates with a loss-of-function for the membrane trafficking steps they are normally involved in, but it also allows them to bind to a novel set of effector proteins with dominant cellular consequences. In this brief review, we will summarize novel findings related to the LRRK2-mediated phosphorylation of Rab GTPases and its various cellular consequences in vitro and in the intact brain, and we will highlight major outstanding questions in the field...

Rubisco activase (RCA) catalyzes the release of inhibitory sugar phosphates from ribulose-1,6-biphosphate carboxylase/oxygenase (Rubisco) and can play an important role in biochemical limitations of photosynthesis under dynamic light and elevated temperatures. There is interest in increasing RCA activity to improve crop productivity, but a lack of understanding about the regulation of photosynthesis complicates engineering strategies. In this review, we discuss work relevant to improving RCA with a focus on advances in understanding the structural cause of RCA instability under heat stress and the regulatory interactions between RCA and components of photosynthesis...

The disruption of chromatin-regulating genes is associated with many neurocognitive syndromes. While most of these genes are ubiquitously expressed across various cell-types, many chromatin regulators act upon activity regulated genes (ARGs) that play central roles in synaptic development and plasticity. Recent literature suggests a link between ARG expression disruption in neurons with the human phenotypes observed in various neurocognitive syndromes. Advances in chromatin biology have demonstrated how chromatin structure, from nucleosome occupancy to higher-order structures such as topologically associated domains, impacts the kinetics of transcription...