1. Structural Biology and Molecular Biophysics

Molecular basis for N-terminal alpha-synuclein acetylation by human NatB

  1. Sunbin Deng
  2. Buyan Pan
  3. Leah Gottlieb
  4. James Petersson
  5. Ronen Marmorstein  Is a corresponding author
  1. Perelman School of Medicine, University of Pennsylvania, United States
  2. University of Pennsylvania, United States
https://doi.org/10.7554/eLife.57491
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  1. Sunbin Deng
  2. Buyan Pan
  3. Leah Gottlieb
  4. James Petersson
  5. Ronen Marmorstein
(2020)
Molecular basis for N-terminal alpha-synuclein acetylation by human NatB
eLife 9:e57491.
https://doi.org/10.7554/eLife.57491
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Abstract

NatB is one of three major N-terminal acetyltransferase (NAT) complexes (NatA-NatC), which co-translationally acetylate the N-termini of eukaryotic proteins. Its substrates account for about 21% of the human proteome, including well known proteins such as actin, tropomyosin, CDK2, and α-synuclein (aSyn). Human NatB (hNatB) mediated N-terminal acetylation of αSyn has been demonstrated to play key roles in Parkinson's disease pathogenesis and as a potential therapeutic target for hepatocellular carcinoma. Here we report the cryo-EM structure of hNatB bound to a CoA-aSyn conjugate, together with structure-guided analysis of mutational effects on catalysis. This analysis reveals functionally important differences with human NatA and Candida albicans NatB, resolves key hNatB protein determinants for aSyn N-terminal acetylation, and identifies important residues for substrate-specific recognition and acetylation by NatB enzymes. These studies have implications for developing small molecule NatB probes and for understanding the mode of substrate selection by NAT enzymes.

Data availability

Cryo-EM data submissions to the Protein Data Bank (PDB code 6VP9), Electron Microscopy Data Bank (EMD code 21307) and Electron Microscopy Public Image Archive (EMPIAR-10477).

The following data sets were generated

Article and author information

Author details

  1. Sunbin Deng

    Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7798-4317

  2. Buyan Pan

    Chemistry, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Leah Gottlieb

    Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. James Petersson

    Chemistry, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Ronen Marmorstein

    Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    For correspondence
    marmor@upenn.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4373-4752

Funding

National Institutes of Health (R35 GM118090)

  • Ronen Marmorstein

National Institutes of Health (R01 NS103873)

  • James Petersson

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

Reviewing Editor

  1. Jeannie Chin, Baylor College of Medicine, United States

Publication history

  1. Received: April 2, 2020
  2. Accepted: September 3, 2020
  3. Accepted Manuscript published: September 4, 2020 (version 1)
  4. Version of Record published: September 16, 2020 (version 2)

Copyright

© 2020, Deng 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. Sunbin Deng
  2. Buyan Pan
  3. Leah Gottlieb
  4. James Petersson
  5. Ronen Marmorstein
(2020)
Molecular basis for N-terminal alpha-synuclein acetylation by human NatB
eLife 9:e57491.
https://doi.org/10.7554/eLife.57491

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