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Biochemical Society transactions.
Portland Press On The Behalf Of The Biochemical Society
Biochemical Society transactions.

Portland Press On The Behalf Of The Biochemical Society

0300-5127

Biochemical Society transactions./Journal Biochemical Society transactions.
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    LILBID-MS: using lasers to shed light on biomolecular architectures

    Hellwig, NilsMartin, JanoschMorgner, Nina
    11页
    查看更多>>摘要：Structural Biology has moved beyond the aim of simply identifying the components of a cellular subsystem towards analysing the dynamics and interactions of multiple players within a cell. This focal shift comes with additional requirements for the analytical tools used to investigate these systems of increased size and complexity, such as Native Mass Spectrometry, which has always been an important tool for structural biology. Scientific advance and recent developments, such as new ways to mimic a cell membrane for a membrane protein, have caused established methods to struggle to keep up with the increased demands. In this review, we summarize the possibilities, which Laser Induced Liquid Bead Ion Desorption (LILBID) mass spectrometry offers with regard to the challenges of modern structural biology, like increasingly complex sample composition, novel membrane mimics and advanced structural analysis, including next neighbor relations and the dynamics of complex formation.
      原文链接:
    • NSTL
    • Portland Press Ltd

    CRISPR/Cas9 and genetic screens in malaria parasites: small genomes, big impact

    Ishizaki, TakahiroHernandez, SophiaPaoletta, Martina S.Sanderson, Theo...
    11页
    查看更多>>摘要：The-30 Mb genomes of the Plasmodium parasites that cause malaria each encode-5000 genes, but the functions of the majority remain unknown. This is due to a paucity of functional annotation from sequence homology, which is compounded by low genetic tractability compared with many model organisms. In recent years technical breakthroughs have made forward and reverse genome-scale screens in Plasmodium possible. Furthermore, the adaptation of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and CRISPR-Associated protein 9 (CRISPR/Cas9) technology has dramatically improved gene editing efficiency at the single gene level. Here, we review the arrival of genetic screens in malaria parasites to analyse parasite gene function at a genome-scale and their impact on understanding parasite biology. CRISPR/Cas9 screens, which have revolutionised human and model organism research, have not yet been implemented in malaria parasites due to the need for more complex CRISPR/Cas9 gene targeting vector libraries. We therefore introduce the reader to CRISPR-based screens in the related apicomplexan Toxoplasma gondii and discuss how these approaches could be adapted to develop CRISPR/Cas9 based genome-scale genetic screens in malaria parasites. Moreover, since more than half of Plasmodium genes are required for normal asexual blood-stage reproduction, and cannot be targeted using knockout methods, we discuss how CRISPR/Cas9 could be used to scale up conditional gene knockdown approaches to systematically assign function to essential genes.
      原文链接:
    • NSTL
    • Portland Press Ltd

    CDK activity sensors: genetically encoded ratiometric biosensors for live analysis of the cell cycle

    Martinez, Michael A. Q.Matus, David Q.
    10页
    查看更多>>摘要：Cyclin-dependent kinase (CDK) sensors have facilitated investigations of the cell cycle in living cells. These genetically encoded fluorescent biosensors change their subcellular location upon activation of CDKs. Activation is primarily regulated by their association with cyclins, which in turn trigger cell-cycle progression. In the absence of CDK activity, cells exit the cell cycle and become quiescent, a key step in stem cell maintenance and cancer cell dormancy. The evolutionary conservation of CDKs has allowed for the rapid development of CDK activity sensors for cell lines and several research organisms, including nematodes, fish, and flies. CDK activity sensors are utilized for their ability to visualize the exact moment of cell-cycle commitment. This has provided a breakthrough in understanding the proliferation-quiescence decision. Further adoption of these biosensors will usher in new discoveries focused on the cell-cycle regulation of development, ageing, and cancer.
      原文链接:
    • NSTL
    • Portland Press Ltd

    Protein-protein and protein-lipid interactions of pore-forming BCL-2 family proteins in apoptosis initiation

    Sekar, GiridharOjoawo, AdedolapoMoldoveanu, Tudor
    13页
    查看更多>>摘要：Apoptosis is a common cell death program that is important in human health and disease. Signaling in apoptosis is largely driven through protein-protein interactions. The BCL-2 family proteins function in protein-protein interactions as key regulators of mitochondrial poration, the process that initiates apoptosis through the release of cytochrome c, which activates the apoptotic caspase cascade leading to cellular demolition. The BCL-2 pore-forming proteins BAK and BAX are the key executors of mitochondrial poration. We review the state of knowledge of protein-protein and protein-lipid interactions governing the apoptotic function of BAK and BAX, as determined through X-ray crystallography and NMR spectroscopy studies. BAK and BAX are dormant, globular alpha-helical proteins that participate in protein-protein interactions with other pro-death BCL-2 family proteins, transforming them into active, partially unfolded proteins that dimerize and associate with and permeabilize mitochondrial membranes. We compare the protein-protein interactions observed in high-resolution structures with those derived in silico by AlphaFold, making predictions based on combining experimental and in silico approaches to delineate the structural basis for novel protein-protein interaction complexes of BCL-2 family proteins.
      原文链接:
    • NSTL
    • Portland Press Ltd

    Clusters of apoptotic signaling molecule-enriched rafts, CASMERs: membrane platforms for protein assembly in Fas/CD95 signaling and targets in cancer therapy

    Mollinedo, FaustinoGajate, Consuelo
    14页
    查看更多>>摘要：Mammalian cells show the ability to commit suicide through the activation of death receptors at the cell surface. Death receptors, among which Fas/CD95 is one of their most representative members, lack enzymatic activity, and depend on protein???protein interactions to signal apoptosis. Fas/CD95 death receptor-mediated apoptosis requires the formation of the so-called death-inducing signaling complex (DISC), bringing together Fas/CD95, Fas-associated death domain-containing protein and procaspase-8. In the last two decades, cholesterol-rich lipid raft platforms have emerged as scaffolds where Fas/CD95 can be recruited and clustered. The co-clustering of Fas/CD95 and rafts facilitates DISC formation, bringing procaspase-8 molecules to be bunched together in a limited membrane region, and leading to their autoproteolytic activation by oligomerization. Lipid raft platforms serve as a specific region for the clustering of Fas/CD95 and DISC, as well as for the recruitment of additional downstream signaling molecules, thus forming the so-called cluster of apoptotic signaling molecule-enriched rafts, or CASMER. These raft/CASMER structures float in the membrane like icebergs, in which the larger portion lies inside the cell and communicates with other subcellular structures to facilitate apoptotic signal transmission. This allows an efficient spatiotemporal compartmentalization of apoptosis signaling machinery during the triggering of cell death. This concept of proapoptotic raft platforms as a basic chemical-biological structure in the regulation of cell death has wide-ranging implications in human biology and disease, as well as in cancer therapy. Here, we discuss how these raft-centered proapoptotic hubs operate as a major linchpin for apoptosis signaling and as a promising target in cancer therapy.
      原文链接:
    • NSTL
    • Portland Press Ltd

    Proteolytic regulation of mitochondrial oxidative phosphorylation components in plants

    Ghifari, Abi S.Murcha, Monika W.
    14页
    查看更多>>摘要：Mitochondrial function relies on the homeostasis and quality control of their proteome, including components of the oxidative phosphorylation (OXPHOS) pathway that generates energy in form of ATP. OXPHOS subunits are under constant exposure to reactive oxygen species due to their oxidation-reduction activities, which consequently make them prone to oxidative damage, misfolding, and aggregation. As a result, quality control mechanisms through turnover and degradation are required for maintaining mitochondrial activity. Degradation of OXPHOS subunits can be achieved through proteomic turnover or modular degradation. In this review, we present multiple protein degradation pathways in plant mitochondria. Specifically, we focus on the intricate turnover of OXPHOS subunits, prior to protein import via cytosolic proteasomal degradation and post import and assembly via intra-mitochondrial proteolysis involving multiple AAA+ proteases. Together, these proteolytic pathways maintain the activity and homeostasis of OXPHOS components.
      原文链接:
    • NSTL
    • Portland Press Ltd

    Host gene effects on gut microbiota in type 1 diabetes

    Guo, KeyuHuang, JuanZhou, Zhiguang
    10页
    查看更多>>摘要：Type 1 diabetes (T1D) is an organ-specific autoimmune disease characterized by progressive pancreatic 0-cell loss. Both a predisposing genetic background, that may encompass mutations in several genes, as well as exposure to environmental factors can affect the progression of autoimmune responses to multiple pancreatic islet autoantigens. Many genetic variants that increase the risk of T1D are found in immunity genes involved in sensing and responding to microorganisms. Although increasing evidence indicates that the gut microbiome composition may promote or prevent T1D development, little is known about the link between gut microbiota and T1D susceptibility genes in patients with T1D. Recent studies in the inbred non-obese diabetic (NOD) mouse, a widely used model of T1D, have suggested that many genetic loci can influence gut microbiome composition to modulate islet autoimmunity. This review summarizes evidence that examines the effect of host genes on gut microbiota diversity and function during T1D development. Knowledge of the host gene-gut microbiota interactions at play during T1D progression may help us identify new diagnostic and prognostic tools and help also design effective strategies for disease treatment.
      原文链接:
    • NSTL
    • Portland Press Ltd

    Role of SWI/SNF chromatin remodeling genes in lung cancer development

    Monterde, BeatrizVarela, Ignacio
    8页
    查看更多>>摘要：SWI/SNF family of chromatin remodeling complexes uses the energy of ATP to change the structure of DNA, playing key roles in DNA regulation and repair. It is estimated that up to 25% of all human cancers contain alterations in SWI/SNF, although the precise molecular mechanisms for their involvement in tumor progression are largely unknown. Despite the improvements achieved in the last decades on our knowledge of lung cancer molecular biology, it remains the major cause of cancer-related deaths worldwide and it is in urgent need for new therapeutic alternatives. We and others have described recurrent alterations in different SWI/SNF genes in nearly 20% of lung cancer patients, some of them with a significant association with worse prognosis, indicating an important role of SWI/SNF in this fatal disease. These alterations might be therapeutically exploited, as it has been shown in cellular and animal models with the use of EGFR inhibitors, DNAdamaging agents and several immunotherapy approaches. Therefore, a better knowledge of the molecular mechanisms regulated by SWI/SNF alterations in lung cancer might be translated into a therapeutic improvement of this frequently lethal disease. In this review, we summarize all the evidence of SWI/SNF alterations in lung cancer, the current knowledge about the potential mechanisms involved in their tumorigenic role, as well as the results that support a potential exploitation of these alterations to improve the treatment of lung cancer patients.
      原文链接:
    • NSTL
    • Portland Press Ltd

    The intersection between circadian and heat-responsive regulatory networks controls plant responses to increasing temperatures

    Laosuntisuk, KanjanaDoherty, Colleen J.
    15页
    查看更多>>摘要：Increasing temperatures impact plant biochemistry, but the effects can be highly variable. Both external and internal factors modulate how plants respond to rising temperatures. One such factor is the time of day or season the temperature increase occurs. This timing significantly affects plant responses to higher temperatures altering the signaling networks and affecting tolerance levels. Increasing overlaps between circadian signaling and high temperature responses have been identified that could explain this sensitivity to the timing of heat stress. ELF3, a circadian clock component, functions as a thermosensor. ELF3 regulates thermoresponsive hypocotyl elongation in part through its cellular localization. The temperature sensitivity of ELF3 depends on the length of a polyglutamine region, explaining how plant temperature responses vary between species. However, the intersection between the circadian system and increased temperature stress responses is pervasive and extends beyond this overlap in thermosensing. Here, we review the network responses to increased temperatures, heat stress, and the impacts on the mechanisms of gene expression from transcription to translation, highlighting the intersections between the elevated temperature and heat stress response pathways and circadian signaling, focusing on the role of ELF3 as a thermosensor.
      原文链接:
    • NSTL
    • Portland Press Ltd

    Investigating chromatin accessibility during development and differentiation by ATAC- sequencing to guide the identification of cis- regulatory elements

    Smith, Emily LouiseMok, Gi FayMunsterberg, Andrea
    11页
    查看更多>>摘要：Mapping accessible chromatin across time scales can give insights into its dynamic nature, for example during cellular differentiation and tissue or organism development. Analysis of such data can be utilised to identify functional cis-regulatory elements (CRE) and transcription factor binding sites and, when combined with transcriptomics, can reveal gene regulatory networks (GRNs) of expressed genes. Chromatin accessibility mapping is a powerful approach and can be performed using ATAC-sequencing (ATAC-seq), whereby Tn5 transposase inserts sequencing adaptors into genomic DNA to iden-tify differentially accessible regions of chromatin in different cell populations. It requires low sample input and can be performed and analysed relatively quickly compared with other methods. The data generated from ATAC-seq, along with other genomic approaches, can help uncover chromatin packaging and potential cis-regulatory elements that may be responsible for gene expression. Here, we describe the ATAC-seq approach and give examples from mainly vertebrate embryonic development, where such datasets have identified the highly dynamic nature of chromatin, with differing landscapes between cellular precursors for different lineages.
      原文链接:
    • NSTL
    • Portland Press Ltd