Two classes of dynein power long-distance cargo transport in different cellular contexts. Cytoplasmic dynein-1 is responsible for the majority of transport toward microtubule minus ends in the cell ...interior. Dynein-2, also known as intraflagellar transport dynein, moves cargoes along the axoneme of eukaryotic cilia and flagella. Both dyneins operate as large ATP-driven motor complexes, whose dysfunction is associated with a group of human disorders. But how similar are their mechanisms of action and regulation? To examine this question, this review focuses on recent advances in dynein-1 and -2 research, and probes to what extent the emerging principles of dynein-1 transport could apply to or differ from those of the less well-understood dynein-2 mechanoenzyme.
Trimethylamine (TMA) N-oxide (TMAO), a gut-microbiota-dependent metabolite, both enhances atherosclerosis in animal models and is associated with cardiovascular risks in clinical studies. Here, we ...investigate the impact of targeted inhibition of the first step in TMAO generation, commensal microbial TMA production, on diet-induced atherosclerosis. A structural analog of choline, 3,3-dimethyl-1-butanol (DMB), is shown to non-lethally inhibit TMA formation from cultured microbes, to inhibit distinct microbial TMA lyases, and to both inhibit TMA production from physiologic polymicrobial cultures (e.g., intestinal contents, human feces) and reduce TMAO levels in mice fed a high-choline or L-carnitine diet. DMB inhibited choline diet-enhanced endogenous macrophage foam cell formation and atherosclerotic lesion development in apolipoprotein e−/− mice without alterations in circulating cholesterol levels. The present studies suggest that targeting gut microbial production of TMA specifically and non-lethal microbial inhibitors in general may serve as a potential therapeutic approach for the treatment of cardiometabolic diseases.
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•Gut microbial trimethylamine lyases are a therapeutic target for atherosclerosis•3,3-dimethyl-1-butanol inhibits microbial trimethylamine formation•3,3-dimethyl-1-butanol attenuates choline diet-enhanced atherosclerosis•Non-lethal gut microbial enzyme inhibition can impact host cardiometabolic phenotypes
Drugging the gut microbiota with a non-lethal inhibitor that blocks production of the metabolite trimethylamine reduces the formation of atherosclerotic lesions and represents the first step toward treatment of cardiometabolic diseases by targeting the microbiome.
The lissencephaly protein Lis1 has been reported to regulate the mechanical behavior of cytoplasmic dynein, the primary minus-end-directed microtubule motor. However, the regulatory mechanism remains ...poorly understood. Here, we address this issue using purified proteins from Saccharomyces cerevisiae and a combination of techniques, including single-molecule imaging and single-particle electron microscopy. We show that rather than binding to the main ATPase site within dynein's AAA+ ring or its microtubule-binding stalk directly, Lis1 engages the interface between these elements. Lis1 causes individual dynein motors to remain attached to microtubules for extended periods, even during cycles of ATP hydrolysis that would canonically induce detachment. Thus, Lis1 operates like a “clutch” that prevents dynein's ATPase domain from transmitting a detachment signal to its track-binding domain. We discuss how these findings provide a conserved mechanism for dynein functions in living cells that require prolonged microtubule attachments.
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► Single-molecule and structural data reveal how Lis1 regulates dynein motility ► Lis1 binds between dynein's ATPase and microtubule-binding domains ► Lis1 alters communication between these elements, prolonging microtubule attachment ► Mutating an arginine finger motif in dynein mimics aspects of Lis1's effect
Lis1 improves dynein processivity by allowing dynein to remain bound to microtubules while it hydrolyzes ATP, a reaction that generally serves to cause motor dissociation.
Fuelled by ATP hydrolysis, dyneins generate force and movement on microtubules in a wealth of biological processes, including ciliary beating, cell division and intracellular transport. The large ...mass and complexity of dynein motors have made elucidating their mechanisms a sizable task. Yet, through a combination of approaches, including X-ray crystallography, cryo-electron microscopy, single-molecule assays and biochemical experiments, important progress has been made towards understanding how these giant motor proteins work. From these studies, a model for the mechanochemical cycle of dynein is emerging, in which nucleotide-driven flexing motions within the AAA+ ring of dynein alter the affinity of its microtubule-binding stalk and reshape its mechanical element to generate movement.
The blood-brain barrier (BBB) poses a unique challenge for drug delivery to the central nervous system (CNS). The BBB consists of a continuous layer of specialized endothelial cells linked together ...by tight junctions, pericytes, nonfenestrated basal lamina, and astrocytic foot processes. This complex barrier controls and limits the systemic delivery of therapeutics to the CNS. Several innovative strategies have been explored to enhance the transport of therapeutics across the BBB, each with individual advantages and disadvantages. Ongoing advances in delivery approaches that overcome the BBB are enabling more effective therapies for CNS diseases. In this review, we discuss: (1) the physiological properties of the BBB, (2) conventional strategies to enhance paracellular and transcellular transport through the BBB, (3) emerging concepts to overcome the BBB, and (4) alternative CNS drug delivery strategies that bypass the BBB entirely. Based on these exciting advances, we anticipate that in the near future, drug delivery research efforts will lead to more effective therapeutic interventions for diseases of the CNS.
Cilia are multifunctional organelles that are constructed using intraflagellar transport (IFT) of cargo to and from their tip. It is widely held that the retrograde IFT motor, dynein-2, must be ...controlled in order to reach the ciliary tip and then unleashed to power the return journey. However, the mechanism is unknown. Here, we systematically define the mechanochemistry of human dynein-2 motors as monomers, dimers, and multimotor assemblies with kinesin-II. Combining these data with insights from single-particle EM, we discover that dynein-2 dimers are intrinsically autoinhibited. Inhibition is mediated by trapping dynein-2's mechanical 'linker' and 'stalk' domains within a novel motor-motor interface. We find that linker-mediated inhibition enables efficient transport of dynein-2 by kinesin-II in vitro. These results suggest a conserved mechanism for autoregulation among dimeric dyneins, which is exploited as a switch for dynein-2's recycling activity during IFT.
Intraflagellar transport (IFT) sculpts the proteome of cilia and flagella; the antenna-like organelles found on the surface of virtually all human cell types. By delivering proteins to the growing ...ciliary tip, recycling turnover products, and selectively transporting signalling molecules, IFT has critical roles in cilia biogenesis, quality control, and signal transduction. IFT involves long polymeric arrays, termed IFT trains, which move to and from the ciliary tip under the power of the microtubule-based motor proteins kinesin-II and dynein-2. Recent top-down and bottom-up structural biology approaches are converging on the molecular architecture of the IFT train machinery. Here we review these studies, with a focus on how kinesin-II and dynein-2 assemble, attach to IFT trains, and undergo precise regulation to mediate bidirectional transport.
Although widely cited as strong evidence that sexual selection has shaped human facial-attractiveness judgments, findings suggesting that women’s preferences for masculine characteristics in men’s ...faces are related to women’s hormonal status are equivocal and controversial. Consequently, we conducted the largest-ever longitudinal study of the hormonal correlates of women’s preferences for facial masculinity (N = 584). Analyses showed no compelling evidence that preferences for facial masculinity were related to changes in women’s salivary steroid hormone levels. Furthermore, both within-subjects and between-subjects comparisons showed no evidence that oral contraceptive use decreased masculinity preferences. However, women generally preferred masculinized over feminized versions of men’s faces, particularly when assessing men’s attractiveness for short-term, rather than long-term, relationships. Our results do not support the hypothesized link between women’s preferences for facial masculinity and their hormonal status.
Cytoplasmic dynein-2 at a glance Vuolo, Laura; Stevenson, Nicola L; Mukhopadhyay, Aakash G ...
Journal of cell science,
03/2020, Volume:
133, Issue:
6
Journal Article
Peer reviewed
Open access
Cytoplasmic dynein-2 is a motor protein complex that drives the movement of cargoes along microtubules within cilia, facilitating the assembly of these organelles on the surface of nearly all ...mammalian cells. Dynein-2 is crucial for ciliary function, as evidenced by deleterious mutations in patients with skeletal abnormalities. Long-standing questions include how the dynein-2 complex is assembled, regulated, and switched between active and inactive states. A combination of model organisms,
cell biology, live-cell imaging, structural biology and biochemistry has advanced our understanding of the dynein-2 motor. In this Cell Science at a Glance article and the accompanying poster, we discuss the current understanding of dynein-2 and its roles in ciliary assembly and function.
Summary Agricultural food production and agriculturally-related change in land use substantially contribute to greenhouse-gas emissions worldwide. Four-fifths of agricultural emissions arise from the ...livestock sector. Although livestock products are a source of some essential nutrients, they provide large amounts of saturated fat, which is a known risk factor for cardiovascular disease. We considered potential strategies for the agricultural sector to meet the target recommended by the UK Committee on Climate Change to reduce UK emissions from the concentrations recorded in 1990 by 80% by 2050, which would require a 50% reduction by 2030. With use of the UK as a case study, we identified that a combination of agricultural technological improvements and a 30% reduction in livestock production would be needed to meet this target; in the absence of good emissions data from Brazil, we assumed for illustrative purposes that the required reductions would be the same for our second case study in São Paulo city. We then used these data to model the potential benefits of reduced consumption of livestock products on the burden of ischaemic heart disease: disease burden would decrease by about 15% in the UK (equivalent to 2850 disability-adjusted life-years DALYs per million population in 1 year) and 16% in São Paulo city (equivalent to 2180 DALYs per million population in 1 year). Although likely to yield benefits to health, such a strategy will probably encounter cultural, political, and commercial resistance, and face technical challenges. Coordinated intersectoral action is needed across agricultural, nutritional, public health, and climate change communities worldwide to provide affordable, healthy, low-emission diets for all societies.