1. Immunology and Inflammation
  2. Structural Biology and Molecular Biophysics

Properdin oligomers adopt rigid extended conformations supporting function

  1. Dennis V Pedersen
  2. Martin N Pedersen
  3. Sofia M Mazarakis
  4. Yong Wang
  5. Kresten Lindorff-Larsen
  6. Lise Arleth
  7. Gregers R Andersen  Is a corresponding author
  1. Aarhus University, Denmark
  2. University of Copenhagen, Denmark
  3. Aarhus Univdersity, Denmark
https://doi.org/10.7554/eLife.63356
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Cite this article
  1. Dennis V Pedersen
  2. Martin N Pedersen
  3. Sofia M Mazarakis
  4. Yong Wang
  5. Kresten Lindorff-Larsen
  6. Lise Arleth
  7. Gregers R Andersen
(2021)
Properdin oligomers adopt rigid extended conformations supporting function
eLife 10:e63356.
https://doi.org/10.7554/eLife.63356
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Abstract

Properdin stabilizes convertases formed upon activation of the complement cascade within the immune system. The biological activity of properdin depends on the oligomerization state, but whether properdin oligomers are rigid and how their structure links to function remains unknown. We show by combining electron microscopy and solution scattering, that properdin oligomers adopt extended rigid and well-defined conformations that are well approximated by single models of apparent n-fold rotational symmetry with dimensions of 230-360 Å. Properdin monomers are pretzel shaped molecules with limited flexibility. In solution, properdin dimers are curved molecules whereas trimers and tetramers are close to being planar molecules. Structural analysis indicates that simultaneous binding through all binding sites to surface linked convertases is unlikely for properdin trimer and tetramers. We show that multivalency alone is insufficient for full activity in a cell lysis assay. Hence, the observed rigid extended oligomer structure is an integral component of properdin function.

Data availability

Scattering data and model for the FP E244K monomer is available as SASBDB entry SASDB69. Scattering data and models for the wild type oligomers are available at SASBDB as entries SASDKA4 (FP2), SASDKB4 (FP3) and SASDKC4 (FP4).

The following data sets were generated

Article and author information

Author details

  1. Dennis V Pedersen

    Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
    Competing interests
    The authors declare that no competing interests exist.

  2. Martin N Pedersen

    Niels Bohr Institute, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    The authors declare that no competing interests exist.

  3. Sofia M Mazarakis

    Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
    Competing interests
    The authors declare that no competing interests exist.

  4. Yong Wang

    Department of Biology, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    The authors declare that no competing interests exist.

  5. Kresten Lindorff-Larsen

    Department of Biology, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4750-6039

  6. Lise Arleth

    Niels Bohr Institute, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    The authors declare that no competing interests exist.

  7. Gregers R Andersen

    Molecular Biology and Genetics, Aarhus Univdersity, Aarhus, Denmark
    For correspondence
    gra@mbg.au.dk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6292-3319

Funding

Lundbeckfonden (R155-2015-2666)

  • Dennis V Pedersen
  • Martin N Pedersen
  • Sofia M Mazarakis
  • Yong Wang
  • Kresten Lindorff-Larsen
  • Lise Arleth
  • Gregers R Andersen

Novo Nordisk Fonden (NNF16OC0022058)

  • Dennis V Pedersen
  • Sofia M Mazarakis
  • Gregers R Andersen

Novo Nordisk Fonden (NF18OC0032608)

  • Kresten Lindorff-Larsen

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Brian V Geisbrecht, Kansas State University, United States

Version history

  1. Received: September 22, 2020
  2. Accepted: January 21, 2021
  3. Accepted Manuscript published: January 22, 2021 (version 1)
  4. Version of Record published: February 3, 2021 (version 2)

Copyright

© 2021, Pedersen et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Dennis V Pedersen
  2. Martin N Pedersen
  3. Sofia M Mazarakis
  4. Yong Wang
  5. Kresten Lindorff-Larsen
  6. Lise Arleth
  7. Gregers R Andersen
(2021)
Properdin oligomers adopt rigid extended conformations supporting function
eLife 10:e63356.
https://doi.org/10.7554/eLife.63356

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