Molecular Bases of Disease
Exosites expedite blood coagulation
A careful balance between active-site and exosite contributions is critically important for the specificity of many proteases, but this balance is not yet defined for some of the serine proteases that serve as coagulation factors. Basavaraj and Krishnaswamy have closed an important gap in our knowledge of coagulation factor X activation by the intrinsic Xase complex by showing that exosite binding plays a critical role in this process, which they describe as a “dock and lock.” This finding not only significantly enhances our understanding of this step in the coagulation cascade and highlights parallels with the prothrombinase complex, but will also provide a novel rationale for inhibitor development in the future.Finding proteases that make cells go viral
The activation of influenza virus hemagglutinin (HA) glycoprotein via cleavage by host cell proteases is essential for viral infectivity, and understanding the mechanisms for HA protein cleavage and how they may differ depending on the biological context is important for the development of flu treatments. However, the HA proteases involved in the activation of many viral strains remain unidentified. In this issue, Harbig et al. identify a repertoire of proteases that cleave HA and determine the proteases' functionality against specific HA glycoproteins.Age matters: Grading granule secretion in beta cells
Insulin is stored in secretory granules to facilitate rapid release in response to rising glucose levels, but the mechanisms by which these granules are identified and prioritized for secretion remains unclear. Using a fluorescent timer and flow cytometry–assisted organelle sorting, Yau et al. develop an elegant approach to assess insulin secretion as a function of granule age in pancreatic islet beta cells. Their findings supply quantitative evidence supporting the age-dependent release of different granule pools and confirm earlier models of preferential release of younger granules.Melding the best of two worlds: Cecil Pickett's work on cellular oxidative stress and in drug discovery and development
Many chemicals and cellular processes cause oxidative stress that can damage lipids, proteins, or DNA (1). To quickly sense and respond to this ubiquitous threat, organisms have evolved enzymes that neutralize harmful oxidants such as reactive oxygen species and electrophilic compounds (including xenobiotics and their breakdown products) in cells.Gained in translation: The power of digging deep into disease models
Mutations affecting the SECISBP2 protein necessary for selenocysteine incorporation are linked to human disease, but with a wide range of clinical outcomes. To gain insight into this diversity, Zhao et al. dissect the phenotypic and molecular consequences of two specific mutations in the Secisbp2 gene that partially disrupt selenoprotein synthesis. They observe surprising tissue-dependent effects, emphasizing the complexities of translational science.Liquid–liquid phase separation of tau protein: The crucial role of electrostatic interactions
Recent studies have indicated that tau, a protein involved in Alzheimer's disease and other neurodegenerative disorders, has a propensity to undergo liquid–liquid phase separation (LLPS). However, the mechanism of this process remains unknown. Here, we demonstrate that tau LLPS is largely driven by intermolecular electrostatic interactions between the negatively charged N-terminal and positively charged middle/C-terminal regions, whereas hydrophobic interactions play a surprisingly small role. Furthermore, our results reveal that, in contrast to previous suggestions, phosphorylation is not required for tau LLPS.Setting fire to fat
Adropin is a liver-secreted peptide that is crucial for metabolic health. However, the molecular functions and clinical significance of adropin have not been adequately explored. Butler et al. now investigate adropin expression profiles and links to cardiometabolic disease risk in two nonhuman primate models, increasing our translational and mechanistic understanding of this fascinating hormone.A promiscuous kinase inhibitor reveals secrets to cancer cell survival
Deregulated kinase signaling networks drive the growth and survival of many cancer cells. However, the genetic complexity and rapidly evolving nature of most cancer cells create challenges when identifying the most relevant kinases to inhibit to achieve optimal therapeutic benefits. A new strategy that takes advantage of a well-characterized multitargeted kinase inhibitor describes a nongenetic approach to tease out key kinases that promote proliferation of specific cancer cell types.Isomerization as the secret Achilles' heel of long-lived proteins
Crystallin proteins, the dominant constituents of the eye lens, are prototypes of long-lived proteins. Such proteins can accumulate harmful modifications over their life span that render them prone to aggregation, which, in the case of lens crystallin, contributes to cataract formation. Lyon et al. now explore the structural and functional consequences of amino acid isomerization in α-crystallins using mass spectrometry, molecular dynamics simulations, and other strategies. Their results highlight the potential deleterious effects of these under-detected modifications on protein structural integrity and function.Celebrating science's next generation
Drum roll, please … It’s time to announce the 2019 group of Herbert Tabor Young Investigator Awardees! Devoted readers of our editorials will know that we recently decided to refocus these awards on the first authors of some of the best work appearing in JBC (1), and we were thrilled to honor the first group of these rising stars in writing (2) and in person at last year’s ASBMB annual meeting. This past fall, we again asked for your help (3) in identifying the most exciting and influential papers published in JBC in 2018 to make sure we were not overlooking any potential awardees.Sweet and CRISP(R)y parasite engineering
Toxoplasma gondii is an intracellular parasite that is highly prevalent within human populations. Its genome encodes a range of enzymes involved in glycan biosynthesis and metabolism. A new study presents a library of CRISPR/Cas9-based glyco-relevant gene knockouts and their examination in glycomic and functional assays. This new resource can pave the way for a better understanding of the role of carbohydrates in infection and immunomodulation by this significant protozoan parasite.A guy with a machine: Using NMR to study biological macromolecules
Hemoglobin was a hot topic in the 1970s. Austrian biochemist Max F. Perutz had shared the Nobel Prize in Chemistry in 1962 for his work mapping the oxygen-transporting metalloprotein's structure. In 1971, U.S. President Richard Nixon called for more research into sickle-cell anemia, a condition caused by abnormal hemoglobin, in his health address to Congress. The National Sickle Cell Anemia Control Act of 1972, passed the following year, encouraged screening, counseling, research, and treatment for the disease.Improving on Nature: James Travis' Work on Recombinant Human α1-Proteinase Inhibitor: Isolation and Properties of Recombinant DNA Produced Variants of Human α -Proteinase Inhibitor
In 1985, when recombinant DNA technology was still in its infancy, James Travis at the University of Georgia and colleagues developed a nonoxidizable form of a protein critical for preventing emphysema. Emphysema is an obstructive lung disease caused by progressive destruction of the lung tissue. The researchers synthesized the natural and variant forms of the protein through a partnership with the biotechnology firm Chiron and then tested it in rabbits to see if it could be used to supplement the protein in patients.
