Abstract：
:The mechanistic Target of Rapamycin Complex 1 (mTORC1) is a major regulator of eukaryotic growth that coordinates anabolic and catabolic cellular processes with inputs such as growth factors and nutrients, including amino acids. In mammals arginine is particularly important, promoting diverse physiological effects such as immune cell activation, insulin secretion, and muscle growth, largely mediated through activation of mTORC1 (refs 4, 5, 6, 7). Arginine activates mTORC1 upstream of the Rag family of GTPases, through either the lysosomal amino acid transporter SLC38A9 or the GATOR2-interacting Cellular Arginine Sensor for mTORC1 (CASTOR1). However, the mechanism by which the mTORC1 pathway detects and transmits this arginine signal has been elusive. Here, we present the 1.8 Å crystal structure of arginine-bound CASTOR1. Homodimeric CASTOR1 binds arginine at the interface of two Aspartate kinase, Chorismate mutase, TyrA (ACT) domains, enabling allosteric control of the adjacent GATOR2-binding site to trigger dissociation from GATOR2 and downstream activation of mTORC1. Our data reveal that CASTOR1 shares substantial structural homology with the lysine-binding regulatory domain of prokaryotic aspartate kinases, suggesting that the mTORC1 pathway exploited an ancient, amino-acid-dependent allosteric mechanism to acquire arginine sensitivity. Together, these results establish a structural basis for arginine sensing by the mTORC1 pathway and provide insights into the evolution of a mammalian nutrient sensor.
journal_name
Naturejournal_title
Natureauthors
Saxton RA,Chantranupong L,Knockenhauer KE,Schwartz TU,Sabatini DMdoi
10.1038/nature19079subject
Has Abstractpub_date
2016-08-11 00:00:00pages
229-33issue
7615eissn
0028-0836issn
1476-4687pii
nature19079journal_volume
536pub_type
杂志文章相关文献
NATURE文献大全abstract：:Mammals form scars to quickly seal wounds and ensure survival by an incompletely understood mechanism1-5. Here we show that skin scars originate from prefabricated matrix in the subcutaneous fascia. Fate mapping and live imaging revealed that fascia fibroblasts rise to the skin surface after wounding, dragging their s...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/s41586-019-1794-y
更新日期：2019-12-01 00:00:00
abstract：:During wild-type development, a protein product of the Caenorhabditis elegans heterochronic gene lin-14 is localized to nuclei of specific somatic cells in embryos and early larvae, but is absent in late larvae and adult soma. Gain-of-function lin-14 mutations cause the level of lin-14 protein to remain high throughou...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/338313a0
更新日期：1989-03-23 00:00:00
abstract：:The histocompatibility-Y (H-Y) antigen is a minor histocompatibility antigen which has been detected on cell surfaces from the heterogametic sexes of mammalian, bird, amphibian, teleost and invertebrate species. H-Y is thought to be a male-determining substance in mammals because of its almost perfect correlation with...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/290503a0
更新日期：1981-04-09 00:00:00
abstract：:Haptic (touch) perception normally entails an active exploration of object surfaces over time. This is called active touch. When exploring the shape of an object, we experience both geometrical and force cues. For example, when sliding a finger across a surface with a rigid bump on it, the finger moves over the bump w...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/35086588
更新日期：2001-07-26 00:00:00
abstract：:Excitatory synaptic transmission in the central nervous system is mediated primarily by the release of glutamate from presynaptic terminals onto postsynaptic channels gated by N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors. The myriad intracellular responses arisi...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/39062
更新日期：1997-10-02 00:00:00
abstract：:The foundation of western civilization owes much to the high fertility of bread wheat, which results from the stability of its polyploid genome. Despite possessing multiple sets of related chromosomes, hexaploid (bread) and tetraploid (pasta) wheat both behave as diploids at meiosis. Correct pairing of homologous chro...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/nature04434
更新日期：2006-02-09 00:00:00
abstract：:The Ndc80 complex is a key site of regulated kinetochore-microtubule attachment (a process required for cell division), but the molecular mechanism underlying its function remains unknown. Here we present a subnanometre-resolution cryo-electron microscopy reconstruction of the human Ndc80 complex bound to microtubules...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/nature09423
更新日期：2010-10-14 00:00:00
abstract：:Mutating the CAACCCCAA sequence in the RNA component of telomerase causes the synthesis in vivo of new telomere sequences corresponding to the mutated RNA sequence, demonstrating that the telomerase contains the template for telomere synthesis. These mutations also lead to nuclear and cell division defects, and senesc...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/344126a0
更新日期：1990-03-08 00:00:00
abstract：:The neurotransmitters glutamate and γ-aminobutyric acid (GABA) transmit synaptic signals by activating fast-acting ligand-gated ion channels and more slowly acting G-protein-coupled receptors (GPCRs). The GPCRs for these neurotransmitters, metabotropic glutamate (mGlu) and GABAB receptors, are atypical GPCRs with a la...
journal_title：Nature
pub_type： 杂志文章,评审
doi：10.1038/nature20566
更新日期：2016-12-01 00:00:00
abstract：:Zygotic genome activation in metazoans typically occurs several hours to a day after fertilization, and thus maternal RNAs and proteins drive early animal embryo development. In plants, despite several molecular studies of post-fertilization transcriptional activation, the timing of zygotic genome activation remains a...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/nature13620
更新日期：2014-10-30 00:00:00
abstract：:Mice express a collection of superantigens, which bind to class II major histocompatibility proteins and interact with T cells bearing particular V beta chains as part of their alpha beta receptors. These superantigens have been suggested to be encoded by exogenous or endogenous mouse mammary tumour viruses. One such ...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/350203a0
更新日期：1991-03-21 00:00:00
abstract：:The fundamental properties of neutron stars provide a direct test of the equation of state of cold nuclear matter, a relationship between pressure and density that is determined by the physics of the strong interactions between the particles that constitute the star. The most straightforward method of determining thes...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/nature01159
更新日期：2002-11-07 00:00:00
abstract：:The antigen CD10 (common acute lymphoblastic leukaemia antigen), which is the zinc metalloprotease, neutral endopeptidase 24.11 (also known as NEP or 'enkephalinase'), is expressed by acute lymphoblastic leukaemias, normal lymphoid progenitors, mature polymorphonuclear leukocytes and certain nonhaematopoietic cells. C...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/347394a0
更新日期：1990-09-27 00:00:00
abstract：:Introns are removed from nuclear messenger RNA precursors through two sequential phospho-transesterification reactions in a dynamic RNA-protein complex called the spliceosome. But whether splicing is catalysed by small nuclear RNAs in the spliceosome is unresolved. As the spliceosome is a metalloenzyme, it is importan...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/35048617
更新日期：2000-12-14 00:00:00
abstract：:Nerve growth factor (NGF) activity was not detected by bioassay in irides killed immediately after excision but NGF appeared within 24 h in living irides placed in culture or grafted to a host eye. Furthermore, sensory and, although less effective, sympathetic denervation of irides in situ led within 10 days to the ap...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/286025a0
更新日期：1980-07-03 00:00:00
abstract：:The site of action of the antispastic drug baclofen has long been considered to reside in the spinal cord although supraspinal effects have also been reported. This beta-chlorophenyl derivative of the neurotransmitter gamma-aminobutyric acid (GABA) depresses both monosynaptic and polysynaptic transmission in the cord ...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/307071a0
更新日期：1984-01-05 00:00:00
abstract：:Transforming growth factor-alpha (TGF-alpha) is a mitogenically active polypeptide hormone produced by acutely proliferating neoplastic and embryonic tissues. Molecular cloning of TGF-alpha cDNA from human and rat has indicated that this factor is synthesized as part of a larger precursor, proTGF-alpha. An intriguing ...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/326883a0
更新日期：1987-04-30 00:00:00
abstract：:The fusion pore is the first crucial intermediate formed during exocytosis, yet little is known about the mechanisms that determine the size and kinetic properties of these transient structures. Here, we reduced the number of available SNAREs (proteins that mediate vesicle fusion) in neurons and observed changes in tr...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/nature25481
更新日期：2018-02-08 00:00:00
abstract：:Integrins are a superfamily of related molecules whose function, where known, is to mediate adhesion. The so-called very-late-activation antigen (VLA) family includes at least five distinct heterodimers, each composed of a unique alpha-subunit non-covalently associated with a common beta-subunit. Several members of th...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/339152a0
更新日期：1989-05-11 00:00:00
abstract：:It is thought that neutron stars in low-mass binary systems can accrete matter and angular momentum from the companion star and be spun-up to millisecond rotational periods. During the accretion stage, the system is called a low-mass X-ray binary, and bright X-ray emission is observed. When the rate of mass transfer d...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/nature12470
更新日期：2013-09-26 00:00:00
abstract：:Here we describe the LifeTime Initiative, which aims to track, understand and target human cells during the onset and progression of complex diseases, and to analyse their response to therapy at single-cell resolution. This mission will be implemented through the development, integration and application of single-cell...
journal_title：Nature
pub_type： 杂志文章,评审
doi：10.1038/s41586-020-2715-9
更新日期：2020-11-01 00:00:00
abstract：:Protecting the world's freshwater resources requires diagnosing threats over a broad range of scales, from global to local. Here we present the first worldwide synthesis to jointly consider human and biodiversity perspectives on water security using a spatial framework that quantifies multiple stressors and accounts f...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/nature09440
更新日期：2010-09-30 00:00:00
abstract：:Guanine-nucleotide exchange factors on ADP-ribosylation factor GTPases (ARF-GEFs) regulate vesicle formation in time and space by activating ARF substrates on distinct donor membranes. Mammalian GBF1 (ref. 2) and yeast Gea1/2 (ref. 3) ARF-GEFs act at Golgi membranes, regulating COPI-coated vesicle formation. In contra...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/nature05967
更新日期：2007-07-26 00:00:00
abstract：:Brain metastasis represents a substantial source of morbidity and mortality in various cancers, and is characterized by high resistance to chemotherapy. Here we define the role of the most abundant cell type in the brain, the astrocyte, in promoting brain metastasis. We show that human and mouse breast and lung cancer...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/nature18268
更新日期：2016-05-26 00:00:00
abstract：:In the prehistoric green Sahara of Holocene North Africa-in contrast to the Neolithic of Europe and Eurasia-a reliance on cattle, sheep and goats emerged as a stable and widespread way of life, long before the first evidence for domesticated plants or settled village farming communities. The remarkable rock art found ...
journal_title：Nature
pub_type： 历史文章,杂志文章
doi：10.1038/nature11186
更新日期：2012-06-20 00:00:00
abstract：:Gravitational lensing is a powerful tool for the study of the distribution of dark matter in the Universe. The cold-dark-matter model of the formation of large-scale structures (that is, clusters of galaxies and even larger assemblies) predicts the existence of quasars gravitationally lensed by concentrations of dark ...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/nature02153
更新日期：2003-12-18 00:00:00
abstract：:To explain the lower atmospheric CO2 concentrations during glacial periods, it has been suggested that the productivity of marine phytoplankton was stimulated by an increased flux of iron-bearing dust to the oceans. One component of this theory is that iron-an essential element/nutrient for nitrogen-fixing organisms-w...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/415156a
更新日期：2002-01-10 00:00:00
abstract：:The unusual helium-rich (type Ib) supernova SN 2005E is distinguished from all supernovae hitherto observed by its faint and rapidly fading light curve, prominent calcium lines in late-phase spectra and lack of any mark of recent star formation near the supernova location. These properties are claimed to be explained ...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/nature09055
更新日期：2010-05-20 00:00:00
abstract：:Alzheimer's disease is the world's most common dementing illness. Deposition of amyloid-β peptide drives cerebral neuroinflammation by activating microglia. Indeed, amyloid-β activation of the NLRP3 inflammasome in microglia is fundamental for interleukin-1β maturation and subsequent inflammatory events. However, it r...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/nature11729
更新日期：2013-01-31 00:00:00
abstract：:The molecular mechanisms controlling the process of myelination by Schwann cells remain elusive, despite recent progress in the identification and characterization of genes encoding myelin components (reviewed in ref. 1). We have created a null allele in the mouse Krox-20 gene, which encodes a zinc-finger transcriptio...
journal_title：Nature
pub_type： 杂志文章
doi：10.1038/371796a0
更新日期：1994-10-27 00:00:00
