Molecular basis for N-terminal alpha-synuclein acetylation by human NatB
- Perelman School of Medicine, University of Pennsylvania, United States
- University of Pennsylvania, United States
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).
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cryo-EM data for NatB complexElectron Microscopy Data Bank, EMD-21307.
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cryo-EM data for NatB compleElectron Microscopy Public Image Archive, 10477.
Article and author information
Author details
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
- Jeannie Chin, Baylor College of Medicine, United States
Publication history
- Received: April 2, 2020
- Accepted: September 3, 2020
- Accepted Manuscript published: September 4, 2020 (version 1)
- 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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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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