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Trends in Biochemical Sciences

Feixiong Cheng, Ruth Nussinov
The underlying genetic causes and altered signaling pathways of brain arteriovenous malformations remain unknown. A study published in The New England Journal of Medicine reported that KRAS somatic mutations (p.Gly12Val/Asp) were identified in brain arteriovenous malformations of human subjects and endothelial cell-enriched cultures, which might specifically activate the MAPK (mitogen-activated protein kinase)-ERK (extracellular signal-regulated kinase) signaling pathway in brain endothelial cells.
May 7, 2018: Trends in Biochemical Sciences
Nicholas R Pannunzio, Michael R Lieber
A subset of chromosomal translocations related to B cell malignancy in human patients arises due to DNA breaks occurring within defined 20-600 base pair (bp) zones. Several factors influence the breakage rate at these sites including transcription, DNA sequence, and topological tension. These factors favor non-B DNA structures that permit formation of transient single-stranded DNA (ssDNA), making the DNA more vulnerable to agents such as the enzyme activation-induced cytidine deaminase (AID) and reactive oxygen species (ROS)...
May 4, 2018: Trends in Biochemical Sciences
Madhu Chaturvedi, Justin Schilling, Alexandre Beautrait, Michel Bouvier, Jeffrey L Benovic, Arun K Shukla
G protein-coupled receptors (GPCRs) recognize a diverse array of extracellular stimuli, and they mediate a broad repertoire of signaling events involved in human physiology. Although the major effort on targeting GPCRs has typically been focused on their extracellular surface, a series of recent developments now unfold the possibility of targeting them from the intracellular side as well. Allosteric modulators binding to the cytoplasmic surface of GPCRs have now been described, and their structural mechanisms are elucidated by high-resolution crystal structures...
May 4, 2018: Trends in Biochemical Sciences
Jianhua Xiong
Mitochondrial fatty acid β-oxidation (FAO) is a major catabolic process that degrades long-chain fatty acids. Recent reports reveal a broad role for FAO in cell fate control in endothelial cells, immune cells, and cancer cells. Concurrently, unique molecular pathways influenced by FAO have been identified that alter cell fate decisions.
May 4, 2018: Trends in Biochemical Sciences
Kendra R Vann, Tatiana G Kutateladze
Polycomb repressive complex 2 (PRC2) is a chief epigenetic regulator. In a new article, Chen et al. describe the crystal structure of the heterotetrameric PRC2 holo complex, which provides important mechanistic insights into the organization of its subunits and the association of PRC2 with chromatin.
May 3, 2018: Trends in Biochemical Sciences
Ebrahim Aboualizadeh, Carol J Hirschmugl
An emerging application of mid-IR spectrochemical imaging of the retina is its utility in studying the highly localized biomolecular alterations in the chemistry of retinal cell layers associated with several pathological conditions. Spatially resolved IR images highlight simultaneous chemical composition of the entire span of the retina in a label-free manner.
May 2, 2018: Trends in Biochemical Sciences
Huan-Xiang Zhou, Valery Nguemaha, Konstantinos Mazarakos, Sanbo Qin
Intracellular membraneless organelles and their myriad cellular functions have garnered tremendous recent interest. It is becoming well accepted that they form via liquid-liquid phase separation (LLPS) of protein mixtures (often including RNA), where the organelles correspond to a protein-rich droplet phase coexisting with a protein-poor bulk phase. The major protein components contain disordered regions and often also RNA-binding domains, and the disordered fragments on their own easily undergo LLPS. By contrast, LLPS for structured proteins has been observed infrequently...
April 28, 2018: Trends in Biochemical Sciences
Caitlyn Q Herr, Robert P Hausinger
Since their discovery in the 1960s, the family of Fe(II)/2-oxoglutarate-dependent oxygenases has undergone a tremendous expansion to include enzymes catalyzing a vast diversity of biologically important reactions. Recent examples highlight roles in controlling chromatin modification, transcription, mRNA demethylation, and mRNA splicing. Others generate modifications in tRNA, translation factors, ribosomes, and other proteins. Thus, oxygenases affect all components of molecular biology's central dogma, in which information flows from DNA to RNA to proteins...
April 27, 2018: Trends in Biochemical Sciences
Kyle P Eagen
Chromosomes are folded and compacted in interphase nuclei, but the molecular basis of this folding is poorly understood. Chromosome conformation capture methods, such as Hi-C, combine chemical crosslinking of chromatin with fragmentation, DNA ligation, and high-throughput DNA sequencing to detect neighboring loci genome-wide. Hi-C has revealed the segregation of chromatin into active and inactive compartments and the folding of DNA into self-associating domains and loops. Depletion of CTCF, cohesin, or cohesin-associated proteins was recently shown to affect the majority of domains and loops in a manner that is consistent with a model of DNA folding through extrusion of chromatin loops...
April 20, 2018: Trends in Biochemical Sciences
Alejandra Medina-Rivera, David Santiago-Algarra, Denis Puthier, Salvatore Spicuglia
Gene expression in higher eukaryotes is precisely regulated in time and space through the interplay between promoters and gene-distal regulatory regions, known as enhancers. The original definition of enhancers implies the ability to activate gene expression remotely, while promoters entail the capability to locally induce gene expression. Despite the conventional distinction between them, promoters and enhancers share many genomic and epigenomic features. One intriguing finding in the gene regulation field comes from the observation that many core promoter regions display enhancer activity...
April 16, 2018: Trends in Biochemical Sciences
Guillermo Rodrigo, Nigel G Stocks
Noise in gene expression is pervasive and, in some cases, even fulfills a functional role. Cancer cell populations exploit noise to increase heterogeneity as a defense against therapies. What lies behind this picture is a phenomenon of stochastic resonance led by the collective, rather than by individual cells.
April 14, 2018: Trends in Biochemical Sciences
A Nilsson, J R Haanstra, B Teusink, J Nielsen
Quantifying the rate of consumption and release of metabolites (i.e., flux profiling) has become integral to the study of cancer. The fluxes as well as the growth of the cells may be affected by metabolite depletion during cultivation.
April 12, 2018: Trends in Biochemical Sciences
Kirstin Gutekunst
All life on earth requires a source of energy and organic carbon. There has been a continuous debate on whether autotrophic or heterotrophic metabolism came first. A very similar discussion exists concerning the advent of oxygenic photosynthesis and aerobic respiration. I put forward the synchronistic evolution hypothesis supposing that all metabolic processes develop in a bidirectional manner from the very first. Bidirectionality is claimed to be intrinsic to the evolution of all metabolic processes as (i) all biochemical reactions and enzymes are per se bidirectional, (ii) substrates need to be regenerated, and (iii) flux regulation requires flexibility of direction...
April 11, 2018: Trends in Biochemical Sciences
Juozas Baltusnikas, Saulius Satkauskas, Kenneth Lundstrom
Long-term transcriptional gene silencing has been hampered by delivery issues. A potential solution is the application of RNA viruses that generate small RNAs without any DNA intermediate. Long-term therapy for various diseases is expected after a single administration.
April 11, 2018: Trends in Biochemical Sciences
Viktoria Klippenstein, Laetitia Mony, Pierre Paoletti
Approaches to remotely control and monitor ion channel operation with light are expanding rapidly in the biophysics and neuroscience fields. A recent development directly introduces light sensitivity into proteins by utilizing photosensitive unnatural amino acids (UAAs) incorporated using the genetic code expansion technique. The introduction of UAAs results in unique molecular level control and, when combined with the maximal spatiotemporal resolution and poor invasiveness of light, enables direct manipulation and interrogation of ion channel functionality...
April 10, 2018: Trends in Biochemical Sciences
Xinran Feng, Shouqing Luo, Boxun Lu
Expanded polyglutamine (polyQ) stretches within endogenous proteins cause at least nine human diseases. The structural basis of polyQ pathogenesis is the key to understanding fundamental mechanisms of these diseases, but it remains unclear and controversial due to a lack of polyQ protein structures at the single-atom level. Various hypotheses have been proposed to explain the structure-cytotoxicity relationship of pathogenic proteins with polyQ expansion, largely based on indirect evidence. Here we review these hypotheses and their supporting evidence, along with additional insights from recent structural biology and chemical biology studies, with a focus on Huntingtin (HTT), the most extensively studied polyQ disease protein...
April 7, 2018: Trends in Biochemical Sciences
Qiuyan Chen, Tina M Iverson, Vsevolod V Gurevich
Arrestins are a small family of proteins with four isoforms in humans. Remarkably, two arrestins regulate signaling from >800 G protein-coupled receptors (GPCRs) or nonreceptor activators by simultaneously binding an activator and one out of hundreds of other signaling proteins. When arrestins are bound to GPCRs or other activators, the affinity for these signaling partners changes. Thus, it is proposed that an activator alters arrestin's ability to transduce a signal. The comparison of all available arrestin structures identifies several common conformational rearrangements associated with activation...
April 7, 2018: Trends in Biochemical Sciences
Catherine L Shelton, Audrey L Lamb
The menaquinone, siderophore, and tryptophan (MST) enzymes transform chorismate to generate precursor molecules for the biosynthetic pathways defined in their name. Kinetic data, both steady-state and transient-state, and X-ray crystal structures indicate that these enzymes are highly conserved both in mechanism and in structure. Because these enzymes are found in pathogens but not in humans, there is considerable interest in these enzymes as drug design targets. While great progress has been made in defining enzyme structure and mechanism, inhibitor design has lagged behind...
March 21, 2018: Trends in Biochemical Sciences
Salvatore Nesci
The molecular structure of the transmembrane domain of ATP synthases is responsible for the inner mitochondrial membrane bending. According to the hypothesized mechanism, ATP synthase dissociation from dimers to monomers, triggered by Ca2+ binding to F1 , allows the mitochondrial permeability transition pore formation at the interface between the detached monomers.
March 16, 2018: Trends in Biochemical Sciences
Stuart Kyle
Affimer proteins can bind to a wide variety of target molecules. They can complement and represent a promising alternative to conventional antibodies as they can target molecules with high affinity, specificity, and stability. In addition, they can be selected and expressed in bacterial and mammalian systems. Affimer protein technology shows promise as a tool in the biologist's arsenal of the future in imaging, diagnostic, and therapeutic applications.
March 14, 2018: Trends in Biochemical Sciences
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