Editors’ Picks, formerly called Papers of the Week, represent the top-rated papers published in JBC across the field of biological chemistry, as determined by our Associate Editors, Editorial Board Members and other referees. These articles—essential for any reading list—are accompanied by additional content summarizing the new findings and featuring the scientists involved.
- Editors' Picks HighlightsMutations 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.
- Editors' Picks HighlightsHomeodomain-interacting protein kinases (HIPKs) are kinases that phosphorylate transcription factors involved in cell proliferation, differentiation, and apoptosis. Their structures have been long sought because of their potential as drug targets in cancers and fibrosis. Agnew and colleagues present the first crystal structure of the HIPK2 kinase domain, complexed with the small-molecule inhibitor CX-4945, revealing important structural differences from related protein kinases of the DYRK family.
- Editors' PicksRecent 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.
- Editors' Picks HighlightsLiquid–liquid phase separation of tau protein has been implicated in normal biological function as well as neurodegenerative diseases, including Alzheimer's. However, knowledge about these links is still scant, and the mechanisms driving tau into liquid droplets are poorly understood. A simplified in vitro system that uses unmodified human tau protein now suggests electrostatic interactions provide the basic instructions underlying liquid droplet formation.
- Editors' Picks HighlightsActivating mutations in protein kinases are a frequent cause of cancer, and selecting drugs that act on these oncogenic kinases can lead to effective therapies. Targeted or whole-genome sequencing of tumor samples can readily reveal the presence of mutations, but discerning previously uncharacterized activating “driver” mutations that will respond to drug treatment from much more abundant but inconsequential “passenger” mutations is problematic. Chakroborty et al. apply a screening approach that leverages error-prone PCR and a proliferating cell model to identify such gain-of-function mutants in the epidermal growth factor receptor (EGFR) kinase.
- Editors' Picks HighlightsDeregulated 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.
- Editors' Picks HighlightsCrystallin 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.
- Editors' Picks Highlights“Myosin” is famous as a component of muscle fibrils, but the majority of myosin family members act elsewhere with roles unrelated to muscle contraction. The biological functions of a relatively new family of these unconventional myosins, myosins 18A and 18B, are poorly understood. New research from Horsthemke et al. describes a new isoform (Myo18Aγ) that is essential for heart function and viability in mice. Their findings both support and contradict other work in the field and raise new questions about the roles of myosin 18 proteins in vivo.
- Editors' Picks HighlightsSmall-molecule inhibitors of histone-modifying enzymes have significant clinical utility for managing diseases such as cancer. These inhibitors are usually identified and monitored through their effects on the gain or loss of specific histone marks. In cells, multiple related enzymes can place or remove a specific mark; therefore, relying on an indirect measure of inhibitor engagement can be misleading. Mascaró et al. describe a luminescence-based ELISA approach that directly monitors binding of inhibitors to the histone lysine demethylase KDM1A.
- Editors' Picks HighlightsT-cell receptors (TCRs) recognize pathogens to ignite immune responses, making them attractive scaffolds for development as immunotherapeutics. However, manipulation of TCRs has been impeded by difficulties in their engineering and expression. Wagner and colleagues now establish new platforms to generate high-affinity TCR variants that potently activate T cells, and they also create soluble TCR fusion proteins that specifically recognize cognate peptides. This work provides specific tools to combat cytomegalovirus (CMV) infection and helps illuminate a general path to actuation of engineered TCR-based therapeutics.
- Editors' Picks HighlightsPoxviruses have evolved efficient proteins that bind mammalian cytokines and chemokines to suppress host immunity. Here Pontejo et al. examine in detail how one such poxviral protein, CrmD, that has activity against both mammalian tumor necrosis factor and chemokines, interacts with its host targets. They apply their findings to refine a human anti-cytokine therapeutic and increase its specificity, providing an elegant example of the benefits of mining viral proteins for therapeutically useful information.
- Editors' Picks HighlightsThe development of genetically engineered proteins that can control cell excitability with light have revolutionized our understanding of the nervous system. The most widely used of these optogenetic tools is the light-gated ion channel, channelrhodopsin 2 (ChR2). A new study by Cho et al. describes the development of ChR2 variants with improved photocurrents and more selective ion permeability using an automated multifaceted fluorescence-based screening. This methodological framework holds promise not only in refining features of ChR2, but also for other proteins in which fluorescence phenotyping is possible.
- Editors' Picks HighlightsDNA double-strand break repair by homologous recombination is initiated by the Ctp1 protein together with the Mre11–Rad50–Nbs1 nuclease complex in Schizosaccharomyces pombe, but the mechanism by which Ctp1 promotes this process has remained unknown. Andres et al. now use atomic force microscopy to image Ctp1–DNA complexes, demonstrating a striking capacity of Ctp1 filaments to bridge DNA molecules. This unanticipated role of Ctp1 might help explain how the processing of DNA ends is coordinated to facilitate DNA break repair.
- Editors' Picks HighlightsThe activity of the archetypal protein kinase A (PKA) is typically thought of in regards to the catalytic subunit, which is inhibited by the regulatory subunits in the absence of cAMP. However, it is now reported that one of the regulatory subunit isoforms (PKA-RIα) takes on a function of its own upon binding to cAMP, acting independently of this canonical cAMP signaling mechanism. PKA-RIα instead binds to and stimulates the catalytic activity of a guanine nucleotide exchange factor (P-REX1) that itself promotes Rac1 GTPase activation.
- Editors' Picks HighlightsNovel imaging techniques with ever-increasing resolution are invaluable tools for the study of protein deposition, as they allow the self-assembly of proteins to be directly investigated in living cells. For the first time, the acceleration in Aβ42 aggregation induced by the Arctic mutation was monitored in cells, revealing a number of distinct morphologies that form sequentially. This approach will help discriminate the impacts of mutations on amyloid protein processing, Aβ aggregation propensity, and other mechanistic outcomes.
- Editors' Picks HighlightsThe basement membrane is a specialized sheet-like form of the extracellular matrix that provides structural support to epithelial cells and tissues, while influencing multiple biological functions, and was essential in the transition to multicellularity. By exploring a variety of genomes, Darris et al. provide evidence that the emergence and divergence of a multifunctional Goodpasture antigen-binding protein (GPBP), a basement membrane constituent, played a role in this transition. These findings help to explain how GPBP contributed to the formation of these extracellular matrices and to more precisely define the transition to multicellular organisms.
- EditorialsA decade ago, the American Journal of Ophthalmology (the Journal) completed a full peer review of almost all submitted manuscripts, feeling it was a responsibility of the Journal. Five years ago, with increasing submissions and a relatively stable, competent peer review pool, the Journal started to triage manuscripts, mainly at the Editor in Chief level, resulting in about 10% of manuscripts rejected at submission, along with a brief note to the authors. Over the past 3 years the Executive Editors have been further empowered to triage manuscripts and to decline further peer review of a manuscript if they are confident that it would not be accepted by the Journal.