scispace - formally typeset
Search or ask a question
Author

Christopher P. Arthur

Bio: Christopher P. Arthur is an academic researcher from Genentech. The author has contributed to research in topics: Medicine & Synaptic vesicle. The author has an hindex of 13, co-authored 27 publications receiving 1063 citations. Previous affiliations of Christopher P. Arthur include Scripps Research Institute & FEI Company.

Papers
More filters
Journal ArticleDOI
06 Aug 2010-Cell
TL;DR: The data show how MAP65s, by combining structural flexibility and rigidity, tune microtubule associations to establish crosslinks that selectively "mark" antiparallel overlap in dynamic cytoskeletal networks.

293 citations

Journal ArticleDOI
23 Aug 2018-Cell
TL;DR: A library consisting of most single transmembrane human receptors is built and a workflow for unbiased and high-sensitivity detection of receptor-ligand interactions is implemented to elucidate the long-sought receptor of human cytomegalovirus (HCMV), the leading viral cause of congenital birth defects.

155 citations

Journal ArticleDOI
22 Mar 2019-Science
TL;DR: Structures reveal how activation of voltage-gated sodium channels causes conformational changes in a voltage-sensor domain, leading to fast inactivation, and pharmacological trapping of VSD4 reveals state-dependent interactions of gating charges from the S4 helix and S4-S5 linker.
Abstract: Fast inactivation of voltage-gated sodium (Nav) channels is essential for electrical signaling, but its mechanism remains poorly understood. Here we determined the structures of a eukaryotic Nav channel alone and in complex with a lethal α-scorpion toxin, AaH2, by electron microscopy, both at 3.5-angstrom resolution. AaH2 wedges into voltage-sensing domain IV (VSD4) to impede fast activation by trapping a deactivated state in which gating charge interactions bridge to the acidic intracellular carboxyl-terminal domain. In the absence of AaH2, the S4 helix of VSD4 undergoes a ~13-angstrom translation to unlatch the intracellular fast-inactivation gating machinery. Highlighting the polypharmacology of α-scorpion toxins, AaH2 also targets an unanticipated receptor site on VSD1 and a pore glycan adjacent to VSD4. Overall, this work provides key insights into fast inactivation, electromechanical coupling, and pathogenic mutations in Nav channels.

124 citations

Journal ArticleDOI
TL;DR: Comparing synaptic transmission in two different hippocampal neuron preparations found that aspects of synaptic transmission differ between autaptic and dissociated cultures, and the synaptic transmission phenotype, resulting from loss of syt-I, is dictated by the connectivity of neurons.
Abstract: Synaptotagmin-I (syt-I) is required for rapid neurotransmitter release in mouse hippocampal neurons. However, contradictory results have been reported regarding evoked and spontaneous secretion from syt-I knock-out (KO) neurons. Here, we compared synaptic transmission in two different hippocampal neuron preparations: autaptic cultures in which a single isolated cell innervates itself, and dissociated mass cultures in which individual cells are innervated by neighboring cells. In autaptic cultures, the total extent of evoked release, size of readily releasable pool of synaptic vesicles, and release probability were unchanged in syt-I KO neurons. In contrast, in cultures containing multiple interconnected neurons, total evoked release, the number of docked vesicles, and release probability, were significantly reduced in syt-I KO neurons. Using a micronetwork system in which we varied the number of cells on an island, we found that the frequency of spontaneous synaptic vesicle fusion events (minis) was unchanged in syt-I KO neurons when two or fewer cells were present on an island. However, in micronetworks composed of three or more neurons, mini frequency was increased threefold to fivefold in syt-I KO neurons compared with wild type. Moreover, interneuronal synapses exhibited higher rates of spontaneous release than autaptic synapses. This higher rate was attributable to an increase in release probability because excitatory hippocampal neurons in micronetworks formed a set number of synapses per cell regardless of the number of connected neurons. Thus, aspects of synaptic transmission differ between autaptic and dissociated cultures, and the synaptic transmission phenotype, resulting from loss of syt-I, is dictated by the connectivity of neurons.

113 citations

ComponentDOI
07 Feb 2019-Cell
TL;DR: ProTx2 from the Peruvian green velvet tarantula is an inhibitor cystine-knot peptide and selective antagonist of the human Nav1.7 channel, providing a structural framework for activation gating in voltage-gated ion channels.

109 citations


Cited by
More filters
01 Jan 2010
TL;DR: In this paper, the authors describe a scenario where a group of people are attempting to find a solution to the problem of "finding the needle in a haystack" in the environment.
Abstract: 中枢神経系疾患の治療は正常細胞(ニューロン)の機能維持を目的とするが,脳血管障害のように機能障害の原因が細胞の死滅に基づくことは多い.一方,脳腫瘍の治療においては薬物療法や放射線療法といった腫瘍細胞の死滅を目標とするものが大きな位置を占める.いずれの場合にも,細胞死の機序を理解することは各種病態や治療法の理解のうえで重要である.現在のところ最も研究の進んでいる細胞死の型はアポトーシスである.そのなかで重要な位置を占めるミトコンドリアにおける反応および抗アポトーシス因子について概要を紹介する.

2,716 citations

Journal ArticleDOI
13 Nov 2020-Science
TL;DR: It is found that neuropilin-1 (NRP1), known to bind furin-cleaved substrates, significantly potentiates SARS-CoV-2 infectivity, an effect blocked by a monoclonal blocking antibody against NRP1.
Abstract: The causative agent of coronavirus disease 2019 (COVID-19) is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For many viruses, tissue tropism is determined by the availability of virus receptors and entry cofactors on the surface of host cells. In this study, we found that neuropilin-1 (NRP1), known to bind furin-cleaved substrates, significantly potentiates SARS-CoV-2 infectivity, an effect blocked by a monoclonal blocking antibody against NRP1. A SARS-CoV-2 mutant with an altered furin cleavage site did not depend on NRP1 for infectivity. Pathological analysis of olfactory epithelium obtained from human COVID-19 autopsies revealed that SARS-CoV-2 infected NRP1-positive cells facing the nasal cavity. Our data provide insight into SARS-CoV-2 cell infectivity and define a potential target for antiviral intervention.

1,304 citations

Journal ArticleDOI
09 Dec 2010-Neuron
TL;DR: A superresolution fluorescence imaging method is presented to visualize the molecular architecture of synapses in the brain using multicolor, three-dimensional stochastic optical reconstruction microscopy, which allows molecular events associated with synaptic plasticity to be resolved at the single-synapse level.

637 citations

Journal ArticleDOI
TL;DR: Non-uniform refinement, an algorithm based on cross-validation optimization, is introduced, which automatically regularizes 3D density maps during refinement to account for spatial variability and yields dramatically improved resolution and 3D map quality in many cases.
Abstract: Cryogenic electron microscopy (cryo-EM) is widely used to study biological macromolecules that comprise regions with disorder, flexibility or partial occupancy. For example, membrane proteins are often kept in solution with detergent micelles and lipid nanodiscs that are locally disordered. Such spatial variability negatively impacts computational three-dimensional (3D) reconstruction with existing iterative refinement algorithms that assume rigidity. We introduce non-uniform refinement, an algorithm based on cross-validation optimization, which automatically regularizes 3D density maps during refinement to account for spatial variability. Unlike common shift-invariant regularizers, non-uniform refinement systematically removes noise from disordered regions, while retaining signal useful for aligning particle images, yielding dramatically improved resolution and 3D map quality in many cases. We obtain high-resolution reconstructions for multiple membrane proteins as small as 100 kDa, demonstrating increased effectiveness of cryo-EM for this class of targets critical in structural biology and drug discovery. Non-uniform refinement is implemented in the cryoSPARC software package. Membrane proteins exhibit spatial variation in rigidity and disorder, which poses a challenge for traditional cryo-EM reconstruction algorithms. Non-uniform refinement accounts for this spatial variability, yielding improved 3D reconstruction quality even for small membrane proteins.

620 citations

Journal ArticleDOI
TL;DR: Topaz as discussed by the authors is an efficient and accurate particle-picking pipeline using neural networks trained with a general-purpose positive-unlabeled learning method, which enables particle detection models to be trained with few sparsely labeled particles and no labeled negatives.
Abstract: Cryo-electron microscopy is a popular method for the determination of protein structures; however, identifying a sufficient number of particles for analysis can take months of manual effort. Current computational approaches find many false positives and require ad hoc postprocessing, especially for unusually shaped particles. To address these shortcomings, we develop Topaz, an efficient and accurate particle-picking pipeline using neural networks trained with a general-purpose positive-unlabeled learning method. This framework enables particle detection models to be trained with few sparsely labeled particles and no labeled negatives. Topaz retrieves many more real particles than conventional picking methods while maintaining low false-positive rates, is capable of picking challenging unusually shaped proteins (for example, small, non-globular and asymmetric particles), produces more representative particle sets and does not require post hoc curation. We demonstrate the performance of Topaz on two difficult datasets and three conventional datasets. Topaz is modular, standalone, free and open source ( http://topaz.csail.mit.edu ).

488 citations