DOI: 10.1073/pnas.1421204112. Structural characterization of toxic oligomers that are kinetically trapped during α-synuclein fibril formation

Structural characterization of toxic oligomers that are kinetically trapped during α-synuclein fibril formation

10.1073/pnas.1421204112

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

Significance Certain oligomeric species generated during the self-assembly of specific proteins into ordered fibrillar aggregates are likely to be key players in the initiation and spreading of neurodegenerative diseases. We have purified stable toxic oligomeric species of α-synuclein and defined and minimized their degree of heterogeneity, which has allowed us to identify distinct subgroups of oligomers and determine their structural properties and three-dimensional molecular architectures. All the oligomeric subgroups possess approximately cylindrical architectures with marked similarities to amyloid fibrils, suggesting that these types of oligomers are kinetically trapped during protein self-assembly. The relative stabilities and inherent pathological roles of different amyloid oligomers are likely to result from the multiplicity of pathways of the misfolding process and the remarkably slow rates of structural conversions.

Bibliography

Chen, S. W., Drakulic, S., Deas, E., Ouberai, M., Aprile, F. A., Arranz, R., Ness, S., Roodveldt, C., Guilliams, T., De-Genst, E. J., Klenerman, D., Wood, N. W., Knowles, T. P. J., Alfonso, C., Rivas, G., Abramov, A. Y., Valpuesta, J. M., Dobson, C. M., & Cremades, N. (2015). Structural characterization of toxic oligomers that are kinetically trapped during Î±-synuclein fibril formation. Proceedings of the National Academy of Sciences, 112(16).

Authors 19

Serene W. Chen (first)
Srdja Drakulic (additional)
Emma Deas (additional)
Myriam Ouberai (additional)
Francesco A. Aprile (additional)
Rocío Arranz (additional)
Samuel Ness (additional)
Cintia Roodveldt (additional)
Tim Guilliams (additional)
Erwin J. De-Genst (additional)
David Klenerman (additional)
Nicholas W. Wood (additional)
Tuomas P.J. Knowles (additional)
Carlos Alfonso (additional)
Germán Rivas (additional)
Andrey Y. Abramov (additional)
José María Valpuesta (additional)
Christopher M. Dobson (additional)
Nunilo Cremades (additional)

References 66 Referenced 323

10.1146/annurev.biochem.75.101304.123901
10.1016/j.cell.2012.02.022
10.1006/jmbi.1997.1348
10.1073/pnas.1219476110
10.1073/pnas.0901085106
10.1038/nrm3810
10.1093/emboj/18.4.815
10.1006/jmbi.1995.0604
10.1006/jmbi.2000.3650
10.1006/jmbi.2000.3908
10.1038/nature05695
10.1126/science.1213151
10.1038/416507a
10.1007/s00109-003-0464-5
10.1523/JNEUROSCI.0615-12.2012
10.1016/j.chembiol.2012.02.003
10.1042/BJ20111924
10.1002/anie.201400491
10.1016/j.jmb.2008.08.039
10.1021/ja9077599
10.1016/j.bbamem.2009.03.010
10.1021/ja411577t
10.1016/j.cell.2012.03.037
10.1021/bi0102398
10.1523/JNEUROSCI.2617-07.2007
10.1021/bi5007833
10.1074/jbc.M114.566695
10.1002/anie.201200813
10.1021/ja412105t
10.1016/S0006-3495(00)76713-0
10.1002/1097-0282(20001015)54:5<328::AID-BIP40>3.0.CO;2-P
10.1007/s002490100176
10.1016/S0022-2836(02)00735-0
10.1074/jbc.M110551200
10.1042/BJ20090379
10.1021/jp4003559
10.1016/j.jmb.2008.06.063
10.1021/bi800279y
10.1073/pnas.0502066102
10.1016/j.febslet.2013.12.015
10.1074/jbc.273.16.9443
10.1016/0163-7827(85)90011-6
10.1016/j.febslet.2011.10.006
10.1074/jbc.M113.478297
10.1016/j.bbamem.2006.02.001
10.1016/0005-2736(95)80035-E
10.1126/science.1079469
10.1021/cb500505m
10.1073/pnas.0712179105
10.1073/pnas.1111305109
10.1016/j.jmb.2003.10.044
10.1038/ncomms6219
10.1007/s00018-007-6525-0
10.1023/B:NERE.0000014834.06405.af
10.1111/j.1742-4658.2006.05234.x
10.1155/2012/428010
10.1016/S0304-3940(02)00016-2
10.2174/0929867053764635
10.1016/j.neuint.2012.11.004
10.1016/S0968-0004(00)01610-8
10.1038/nature02261
10.1021/bi300558q
10.1016/j.bpj.2013.04.050
TM Laue, BD Shah, TM Ridgeway, SL Pelletier, Computer-aided interpretation of analytical sedimentation data for proteins. Analytical Ultracentrifugation in Biochemistry and Polymer Science, eds SE Harding, AJ Rowe, JC Horton (Roy Soc Chem, Cambridge, UK), pp. 90–125 (1992). / Analytical Ultracentrifugation in Biochemistry and Polymer Science by Laue TM (1992)
10.1006/jsbi.1996.0036
10.1006/jsbi.1999.4174

Dates

Type	When
Created	10 years, 4 months ago (April 8, 2015, 11:18 p.m.)
Deposited	3 years, 4 months ago (April 13, 2022, 12:16 a.m.)
Indexed	4 minutes ago (Aug. 26, 2025, 2:40 a.m.)
Issued	10 years, 4 months ago (April 8, 2015)
Published	10 years, 4 months ago (April 8, 2015)
Published Online	10 years, 4 months ago (April 8, 2015)
Published Print	10 years, 4 months ago (April 21, 2015)

Funders 0

None

BibTeX

@article{Chen_2015, title={Structural characterization of toxic oligomers that are kinetically trapped during α-synuclein fibril formation}, volume={112}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.1421204112}, DOI={10.1073/pnas.1421204112}, number={16}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Chen, Serene W. and Drakulic, Srdja and Deas, Emma and Ouberai, Myriam and Aprile, Francesco A. and Arranz, Rocío and Ness, Samuel and Roodveldt, Cintia and Guilliams, Tim and De-Genst, Erwin J. and Klenerman, David and Wood, Nicholas W. and Knowles, Tuomas P.J. and Alfonso, Carlos and Rivas, Germán and Abramov, Andrey Y. and Valpuesta, José María and Dobson, Christopher M. and Cremades, Nunilo}, year={2015}, month=apr }

JSON

{
  "indexed": {
    "date-parts": [
      [
        2025,
        8,
        26
      ]
    ],
    "date-time": "2025-08-26T06:40:52Z",
    "timestamp": 1756190452669
  },
  "reference-count": 66,
  "publisher": "Proceedings of the National Academy of Sciences",
  "issue": "16",
  "content-domain": {
    "domain": [
      "www.pnas.org"
    ],
    "crossmark-restriction": true
  },
  "published-print": {
    "date-parts": [
      [
        2015,
        4,
        21
      ]
    ]
  },
  "abstract": "<jats:title>Significance</jats:title>\n          <jats:p>Certain oligomeric species generated during the self-assembly of specific proteins into ordered fibrillar aggregates are likely to be key players in the initiation and spreading of neurodegenerative diseases. We have purified stable toxic oligomeric species of \u03b1-synuclein and defined and minimized their degree of heterogeneity, which has allowed us to identify distinct subgroups of oligomers and determine their structural properties and three-dimensional molecular architectures. All the oligomeric subgroups possess approximately cylindrical architectures with marked similarities to amyloid fibrils, suggesting that these types of oligomers are kinetically trapped during protein self-assembly. The relative stabilities and inherent pathological roles of different amyloid oligomers are likely to result from the multiplicity of pathways of the misfolding process and the remarkably slow rates of structural conversions.</jats:p>",
  "DOI": "10.1073/pnas.1421204112",
  "type": "journal-article",
  "created": {
    "date-parts": [
      [
        2015,
        4,
        9
      ]
    ],
    "date-time": "2015-04-09T03:18:53Z",
    "timestamp": 1428549533000
  },
  "update-policy": "http://dx.doi.org/10.1073/pnas.cm10313",
  "source": "Crossref",
  "is-referenced-by-count": 323,
  "title": "Structural characterization of toxic oligomers that are kinetically trapped during \u03b1-synuclein fibril formation",
  "prefix": "10.1073",
  "volume": "112",
  "author": [
    {
      "given": "Serene W.",
      "family": "Chen",
      "sequence": "first",
      "affiliation": [
        {
          "name": "Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom;"
        }
      ]
    },
    {
      "given": "Srdja",
      "family": "Drakulic",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Department of Macromolecular Structure, Centro Nacional de Biotecnolog\u00eda (CNB-CSIC), 28049 Madrid, Spain;"
        }
      ]
    },
    {
      "given": "Emma",
      "family": "Deas",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Department of Molecular Neuroscience, University College London, Institute of Neurology, London WC1N 3BG, United Kingdom;"
        }
      ]
    },
    {
      "given": "Myriam",
      "family": "Ouberai",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Nanoscience Centre, Department of Engineering, University of Cambridge, Cambridge CB3 0FF, United Kingdom;"
        }
      ]
    },
    {
      "given": "Francesco A.",
      "family": "Aprile",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom;"
        }
      ]
    },
    {
      "given": "Roc\u00edo",
      "family": "Arranz",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Department of Macromolecular Structure, Centro Nacional de Biotecnolog\u00eda (CNB-CSIC), 28049 Madrid, Spain;"
        }
      ]
    },
    {
      "given": "Samuel",
      "family": "Ness",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom;"
        }
      ]
    },
    {
      "given": "Cintia",
      "family": "Roodveldt",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Department of Cellular Therapy and Regenerative Medicine, Andalusian Center for Molecular Biology and Regenerative Medicine, 41092 Seville, Spain; and"
        }
      ]
    },
    {
      "given": "Tim",
      "family": "Guilliams",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom;"
        }
      ]
    },
    {
      "given": "Erwin J.",
      "family": "De-Genst",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom;"
        }
      ]
    },
    {
      "given": "David",
      "family": "Klenerman",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom;"
        }
      ]
    },
    {
      "given": "Nicholas W.",
      "family": "Wood",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Department of Molecular Neuroscience, University College London, Institute of Neurology, London WC1N 3BG, United Kingdom;"
        }
      ]
    },
    {
      "given": "Tuomas P.J.",
      "family": "Knowles",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom;"
        }
      ]
    },
    {
      "given": "Carlos",
      "family": "Alfonso",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Department of Cellular and Molecular Biology, Centro de Investigaciones Biol\u00f3gicas (CIB-CSIC), 28040 Madrid, Spain"
        }
      ]
    },
    {
      "given": "Germ\u00e1n",
      "family": "Rivas",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Department of Cellular and Molecular Biology, Centro de Investigaciones Biol\u00f3gicas (CIB-CSIC), 28040 Madrid, Spain"
        }
      ]
    },
    {
      "given": "Andrey Y.",
      "family": "Abramov",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Department of Molecular Neuroscience, University College London, Institute of Neurology, London WC1N 3BG, United Kingdom;"
        }
      ]
    },
    {
      "given": "Jos\u00e9 Mar\u00eda",
      "family": "Valpuesta",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Department of Macromolecular Structure, Centro Nacional de Biotecnolog\u00eda (CNB-CSIC), 28049 Madrid, Spain;"
        }
      ]
    },
    {
      "given": "Christopher M.",
      "family": "Dobson",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom;"
        }
      ]
    },
    {
      "given": "Nunilo",
      "family": "Cremades",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom;"
        }
      ]
    }
  ],
  "member": "341",
  "published-online": {
    "date-parts": [
      [
        2015,
        4,
        8
      ]
    ]
  },
  "reference": [
    {
      "key": "e_1_3_3_1_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1146/annurev.biochem.75.101304.123901"
    },
    {
      "key": "e_1_3_3_2_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/j.cell.2012.02.022"
    },
    {
      "key": "e_1_3_3_3_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1006/jmbi.1997.1348"
    },
    {
      "key": "e_1_3_3_4_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.1219476110"
    },
    {
      "key": "e_1_3_3_5_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.0901085106"
    },
    {
      "key": "e_1_3_3_6_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/nrm3810"
    },
    {
      "key": "e_1_3_3_7_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1093/emboj/18.4.815"
    },
    {
      "key": "e_1_3_3_8_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1006/jmbi.1995.0604"
    },
    {
      "key": "e_1_3_3_9_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1006/jmbi.2000.3650"
    },
    {
      "key": "e_1_3_3_10_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1006/jmbi.2000.3908"
    },
    {
      "key": "e_1_3_3_11_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/nature05695"
    },
    {
      "key": "e_1_3_3_12_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1126/science.1213151"
    },
    {
      "key": "e_1_3_3_13_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/416507a"
    },
    {
      "key": "e_1_3_3_14_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1007/s00109-003-0464-5"
    },
    {
      "key": "e_1_3_3_15_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1523/JNEUROSCI.0615-12.2012"
    },
    {
      "key": "e_1_3_3_16_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/j.chembiol.2012.02.003"
    },
    {
      "key": "e_1_3_3_17_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1042/BJ20111924"
    },
    {
      "key": "e_1_3_3_18_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1002/anie.201400491"
    },
    {
      "key": "e_1_3_3_19_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/j.jmb.2008.08.039"
    },
    {
      "key": "e_1_3_3_20_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1021/ja9077599"
    },
    {
      "key": "e_1_3_3_21_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/j.bbamem.2009.03.010"
    },
    {
      "key": "e_1_3_3_22_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1021/ja411577t"
    },
    {
      "key": "e_1_3_3_23_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/j.cell.2012.03.037"
    },
    {
      "key": "e_1_3_3_24_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1021/bi0102398"
    },
    {
      "key": "e_1_3_3_25_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1523/JNEUROSCI.2617-07.2007"
    },
    {
      "key": "e_1_3_3_26_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1021/bi5007833"
    },
    {
      "key": "e_1_3_3_27_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.M114.566695"
    },
    {
      "key": "e_1_3_3_28_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1002/anie.201200813"
    },
    {
      "key": "e_1_3_3_29_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1021/ja412105t"
    },
    {
      "key": "e_1_3_3_30_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0006-3495(00)76713-0"
    },
    {
      "key": "e_1_3_3_31_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1002/1097-0282(20001015)54:5<328::AID-BIP40>3.0.CO;2-P"
    },
    {
      "key": "e_1_3_3_32_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1007/s002490100176"
    },
    {
      "key": "e_1_3_3_33_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0022-2836(02)00735-0"
    },
    {
      "key": "e_1_3_3_34_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.M110551200"
    },
    {
      "key": "e_1_3_3_35_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1042/BJ20090379"
    },
    {
      "key": "e_1_3_3_36_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1021/jp4003559"
    },
    {
      "key": "e_1_3_3_37_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/j.jmb.2008.06.063"
    },
    {
      "key": "e_1_3_3_38_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1021/bi800279y"
    },
    {
      "key": "e_1_3_3_39_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.0502066102"
    },
    {
      "key": "e_1_3_3_40_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/j.febslet.2013.12.015"
    },
    {
      "key": "e_1_3_3_41_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.273.16.9443"
    },
    {
      "key": "e_1_3_3_42_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0163-7827(85)90011-6"
    },
    {
      "key": "e_1_3_3_43_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/j.febslet.2011.10.006"
    },
    {
      "key": "e_1_3_3_44_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.M113.478297"
    },
    {
      "key": "e_1_3_3_45_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/j.bbamem.2006.02.001"
    },
    {
      "key": "e_1_3_3_46_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0005-2736(95)80035-E"
    },
    {
      "key": "e_1_3_3_47_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1126/science.1079469"
    },
    {
      "key": "e_1_3_3_48_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1021/cb500505m"
    },
    {
      "key": "e_1_3_3_49_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.0712179105"
    },
    {
      "key": "e_1_3_3_50_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.1111305109"
    },
    {
      "key": "e_1_3_3_51_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/j.jmb.2003.10.044"
    },
    {
      "key": "e_1_3_3_52_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/ncomms6219"
    },
    {
      "key": "e_1_3_3_53_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1007/s00018-007-6525-0"
    },
    {
      "key": "e_1_3_3_54_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1023/B:NERE.0000014834.06405.af"
    },
    {
      "key": "e_1_3_3_55_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1111/j.1742-4658.2006.05234.x"
    },
    {
      "key": "e_1_3_3_56_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1155/2012/428010"
    },
    {
      "key": "e_1_3_3_57_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0304-3940(02)00016-2"
    },
    {
      "key": "e_1_3_3_58_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.2174/0929867053764635"
    },
    {
      "key": "e_1_3_3_59_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/j.neuint.2012.11.004"
    },
    {
      "key": "e_1_3_3_60_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0968-0004(00)01610-8"
    },
    {
      "key": "e_1_3_3_61_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/nature02261"
    },
    {
      "key": "e_1_3_3_62_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1021/bi300558q"
    },
    {
      "key": "e_1_3_3_63_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/j.bpj.2013.04.050"
    },
    {
      "key": "e_1_3_3_64_2",
      "first-page": "90",
      "volume-title": "Analytical Ultracentrifugation in Biochemistry and Polymer Science",
      "author": "Laue TM",
      "year": "1992",
      "unstructured": "TM Laue, BD Shah, TM Ridgeway, SL Pelletier, Computer-aided interpretation of analytical sedimentation data for proteins. Analytical Ultracentrifugation in Biochemistry and Polymer Science, eds SE Harding, AJ Rowe, JC Horton (Roy Soc Chem, Cambridge, UK), pp. 90\u2013125 (1992)."
    },
    {
      "key": "e_1_3_3_65_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1006/jsbi.1996.0036"
    },
    {
      "key": "e_1_3_3_66_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1006/jsbi.1999.4174"
    }
  ],
  "container-title": "Proceedings of the National Academy of Sciences",
  "original-title": [],
  "language": "en",
  "link": [
    {
      "URL": "https://pnas.org/doi/pdf/10.1073/pnas.1421204112",
      "content-type": "unspecified",
      "content-version": "vor",
      "intended-application": "similarity-checking"
    }
  ],
  "deposited": {
    "date-parts": [
      [
        2022,
        4,
        13
      ]
    ],
    "date-time": "2022-04-13T04:16:46Z",
    "timestamp": 1649823406000
  },
  "score": 1,
  "resource": {
    "primary": {
      "URL": "https://pnas.org/doi/full/10.1073/pnas.1421204112"
    }
  },
  "subtitle": [],
  "short-title": [],
  "issued": {
    "date-parts": [
      [
        2015,
        4,
        8
      ]
    ]
  },
  "references-count": 66,
  "journal-issue": {
    "issue": "16",
    "published-print": {
      "date-parts": [
        [
          2015,
          4,
          21
        ]
      ]
    }
  },
  "alternative-id": [
    "10.1073/pnas.1421204112"
  ],
  "URL": "http://dx.doi.org/10.1073/pnas.1421204112",
  "relation": {
    "has-review": [
      {
        "id-type": "doi",
        "id": "10.3410/f.725428482.793530666",
        "asserted-by": "object"
      },
      {
        "id-type": "doi",
        "id": "10.3410/f.725428482.793519823",
        "asserted-by": "object"
      }
    ]
  },
  "ISSN": [
    "0027-8424",
    "1091-6490"
  ],
  "subject": [],
  "container-title-short": "Proc. Natl. Acad. Sci. U.S.A.",
  "published": {
    "date-parts": [
      [
        2015,
        4,
        8
      ]
    ]
  },
  "assertion": [
    {
      "value": "2015-04-08",
      "order": 2,
      "name": "published",
      "label": "Published",
      "group": {
        "name": "publication_history",
        "label": "Publication History"
      }
    }
  ]
}