Abstract:
:Exchange dynamics between molecules free in solution and bound to the surface of a large supramolecular structure, a polymer, a membrane or solid support are important in many phenomena in biology and materials science. Here we present a novel and generally applicable solution NMR technique, known as dark-state exchange saturation transfer (DEST), to probe such exchange phenomena with atomic resolution. This is illustrated by the exchange reaction between amyloid-β (Aβ) monomers and polydisperse, NMR-invisible ('dark') protofibrils, a process of significant interest because the accumulation of toxic, aggregated forms of Aβ, from small oligomers to very large assemblies, has been implicated in the aetiology of Alzheimer's disease. The (15)N-DEST experiment imprints with single-residue-resolution dynamic information on the protofibril-bound species in the form of (15)N transverse relaxation rates ((15)N-R(2)) and exchange kinetics between monomers and protofibrils onto the easily observed two-dimensional (1)H-(15)N correlation spectrum of the monomer. The exchanging species on the protofibril surface comprise an ensemble of sparsely populated states where each residue is either tethered to (through other residues) or in direct contact with the surface. The first eight residues exist predominantly in a mobile tethered state, whereas the largely hydrophobic central region and part of the carboxy (C)-terminal hydrophobic region are in direct contact with the protofibril surface for a significant proportion of the time. The C-terminal residues of both Aβ40 and Aβ42 display lower affinity for the protofibril surface, indicating that they are likely to be surface exposed rather than buried as in structures of Aβ fibrils, and might therefore comprise the critical nucleus for fibril formation. The values, however, are significantly larger for the C-terminal residues of Aβ42 than Aβ40, which might explain the former's higher propensity for rapid aggregation and fibril formation.
journal_name
Naturejournal_title
Natureauthors
Fawzi NL,Ying J,Ghirlando R,Torchia DA,Clore GMdoi
10.1038/nature10577subject
Has Abstractpub_date
2011-10-30 00:00:00pages
268-72issue
7376eissn
0028-0836issn
1476-4687pii
nature10577journal_volume
480pub_type
杂志文章相关文献
NATURE文献大全abstract::A wide range of receptors are located at the blood sinusoidal aspect of the hepatocyte plasma membrane. Many circulating ligands that bind to receptors on the cell surfaces are interiorized along two pathways. Asialoglycoproteins are transferred from the plasma membrane to lysosomes and degraded, whereas immunoglobuli...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/298398a0
更新日期:1982-07-22 00:00:00
abstract::The eukaryotic cell cycle comprises an ordered series of events, orchestrated by the activity of cyclin-dependent kinases (Cdks), leading from chromosome replication during S phase to their segregation in mitosis. The unidirectionality of cell-cycle transitions is fundamental for the successful completion of this cycl...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature07984
更新日期:2009-05-28 00:00:00
abstract::An ageing world population has fuelled interest in regenerative remedies that may stem declining organ function and maintain fitness. Unanswered is whether elimination of intrinsic instigators driving age-associated degeneration can reverse, as opposed to simply arrest, various afflictions of the aged. Such instigator...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature09603
更新日期:2011-01-06 00:00:00
abstract::Ice sheets are currently ignored in global methane budgets1,2. Although ice sheets have been proposed to contain large reserves of methane that may contribute to a rise in atmospheric methane concentration if released during periods of rapid ice retreat3,4, no data exist on the current methane footprint of ice sheets....
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/s41586-018-0800-0
更新日期:2019-01-01 00:00:00
abstract::Polycomb group proteins have an essential role in the epigenetic maintenance of repressive chromatin states. The gene-silencing activity of the Polycomb repressive complex 2 (PRC2) depends on its ability to trimethylate lysine 27 of histone H3 (H3K27) by the catalytic SET domain of the EZH2 subunit, and at least two o...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature08398
更新日期:2009-10-08 00:00:00
abstract::The Yorkie homologues YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif, also known as WWTR1), effectors of the Hippo pathway, have been identified as mediators for mechanical stimuli. However, the role of YAP/TAZ in haemodynamics-induced mechanotransduction and pathogenesis of a...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature20602
更新日期:2016-12-22 00:00:00
abstract:: ...
journal_title:Nature
pub_type: 评论,社论
doi:10.1038/d41586-019-00483-5
更新日期:2019-02-01 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::Sounds heard over headphones are typically perceived inside the head (internalized), unlike real sound sources which are perceived outside the head (externalized). If the acoustical waveforms from a real sound source are reproduced precisely using headphones, auditory images are appropriately externalized and localize...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/25526
更新日期:1998-12-24 00:00:00
abstract::Macrophages and dendritic cells have key roles in viral infections, providing virus reservoirs that frequently resist antiviral therapies and linking innate virus detection to antiviral adaptive immune responses. Human immunodeficiency virus 1 (HIV-1) fails to transduce dendritic cells and has a reduced ability to tra...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature10195
更新日期:2011-06-29 00:00:00
abstract::The debate over human origins has focused on two competing theories. The single African origin model holds that anatomically modern Homo sapiens evolved in Africa 100,000-200,000 years ago. Members of this population migrated out of Africa, replacing archaic human groups through Asia and Europe, with racial differenti...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/368452a0
更新日期:1994-03-31 00:00:00
abstract::The Encyclopedia of DNA Elements (ENCODE) project has established a genomic resource for mammalian development, profiling a diverse panel of mouse tissues at 8 developmental stages from 10.5 days after conception until birth, including transcriptomes, methylomes and chromatin states. Here we systematically examined th...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/s41586-020-2093-3
更新日期:2020-07-01 00:00:00
abstract:: ...
journal_title:Nature
pub_type: 社论
doi:10.1038/d41586-018-07151-0
更新日期:2018-10-01 00:00:00
abstract::Metabotropic γ-aminobutyric acid receptors (GABAB) are involved in the modulation of synaptic responses in the central nervous system and have been implicated in neuropsychological conditions that range from addiction to psychosis1. GABAB belongs to class C of the G-protein-coupled receptors, and its functional entity...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/s41586-020-2408-4
更新日期:2020-08-01 00:00:00
abstract::Although the link between long gamma-ray bursts (GRBs) and supernovae has been established, hitherto there have been no observations of the beginning of a supernova explosion and its intimate link to a GRB. In particular, we do not know how the jet that defines a gamma-ray burst emerges from the star's surface, nor ho...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature04892
更新日期:2006-08-31 00:00:00
abstract::The Gulf Stream transports large amounts of heat from the tropics to middle and high latitudes, and thereby affects weather phenomena such as cyclogenesis and low cloud formation. But its climatic influence, on monthly and longer timescales, remains poorly understood. In particular, it is unclear how the warm current ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature06690
更新日期:2008-03-13 00:00:00
abstract::Plants can have positive effects on each other. For example, the accumulation of nutrients, provision of shade, amelioration of disturbance, or protection from herbivores by some species can enhance the performance of neighbouring species. Thus the notion that the distributions and abundances of plant species are inde...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature00812
更新日期:2002-06-20 00:00:00
abstract::Mammal-like reptiles of the order Therapsida document the emergence of mammals from more primitive synapsids and are of unique zoological and palaeontological interest on that account. Therapsids, first appearing in the Early Permian, were thought to become extinct in the Middle Jurassic, soon after the Late Triassic ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/358233a0
更新日期:1992-07-16 00:00:00
abstract::Haem is essential for living organisms, functioning as a crucial element in the redox-sensitive reaction centre in haemproteins. During the biogenesis of these proteins, the haem cofactor is typically incorporated enzymatically into the haem pockets of the apo-haemprotein as the functionally indispensable prosthetic g...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature02003
更新日期:2003-10-02 00:00:00
abstract::The classical theory of solids, based on the quantum mechanics of single electrons moving in periodic potentials, provides an excellent description of substances ranging from semiconducting silicon to superconducting aluminium. Over the last fifteen years, it has become increasingly clear that there are substances for...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature01044
更新日期:2002-10-03 00:00:00
abstract::DNA replication in eukaryotes is strictly regulated by several mechanisms. A central step in this replication is the assembly of the heterohexameric minichromosome maintenance (MCM2-7) helicase complex at replication origins during G1 phase as an inactive double hexamer. Here, using cryo-electron microscopy, we report...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature14685
更新日期:2015-08-13 00:00:00
abstract::Neurons develop a highly polarized morphology consisting of dendrites and a long axon. Both axons and dendrites contain microtubules and microtubule-associated proteins (MAPs) with characteristic structures. Among MAPs, MAP2 is specifically expressed in dendrites whereas MAP2C and tau are abundant in the axon. But the...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/360674a0
更新日期:1992-12-17 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::A hemispheric dichotomy on Mars is marked by the sharp contrast between the sparsely cratered northern lowland plains and the heavily cratered southern highlands. Mechanisms proposed to remove ancient crust or form younger lowland crust include one or more giant impacts, subcrustal transport by mantle convection, the ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature05356
更新日期:2006-12-14 00:00:00
abstract::A major aim in immunology has been to understand how the immune system evokes characteristic responses to infection, foreign tissue grafts and tumours. The current view of immunoregulation is based mainly on studies of lymphocyte subsets, either in vitro or by adoptive transfer to irradiated recipients. Many reagents ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/312548a0
更新日期:1984-12-06 00:00:00
abstract::Hepatocellularcarcinoma (HCC) that occur in woodchucks chronically infected with woodchuck hepatitis virus (WHV) were screened for activation of cellular oncogenes. Enhanced expression and allelic alterations of the c-myc oncogene were found in three HCC out of nine. Variations in the size of the c-myc transcripts, ra...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/324276a0
更新日期:1986-11-20 00:00:00
abstract::Excitatory amino acids induce both acute membrane depolarization and latent cellular toxicity, which often leads to apoptosis in many neurological disorders. Recent studies indicate that glutamate toxicity may involve the c-Jun amino-terminal kinase (JNK) group of mitogen-activated protein (MAP) kinases. One member of...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/39899
更新日期:1997-10-23 00:00:00
abstract::A single U leads to G transversion in the 3' consensus sequence AAUAAA of the adenovirus early region 1A gene was constructed and the effect of this mutation on processing of the 3' end of the nuclear early region 1A RNAs was analysed. The results demonstrate that the intact AAUAAA is not required for RNA polyadenylat...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/305600a0
更新日期:1983-10-13 00:00:00
abstract::Do biological motors move with regular steps? To address this question, we constructed instrumentation with the spatial and temporal sensitivity to resolve movement on a molecular scale. We deposited silica beads carrying single molecules of the motor protein kinesin on microtubules using optical tweezers and analysed...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/365721a0
更新日期:1993-10-21 00:00:00
abstract::Recognition of sweet, bitter and umami tastes requires the non-vesicular release from taste bud cells of ATP, which acts as a neurotransmitter to activate afferent neural gustatory pathways. However, how ATP is released to fulfil this function is not fully understood. Here we show that calcium homeostasis modulator 1 ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature11906
更新日期:2013-03-14 00:00:00