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

Abstract
Data availability
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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

1. Deng S
2. Marmorstein R
(2020) Cryo-EM structure of human NatB complex
Protein Data Bank, 6VP9.

http://www.rcsb.org/structure/6VP9
1. Deng S
2. Marmorstein R
(2020) cryo-EM data for NatB complex
Electron Microscopy Data Bank, EMD-21307.

http://www.ebi.ac.uk/pdbe/entry/emdb/EMD-21307
1. Deng S
2. Marmorstein R
(2020) cryo-EM data for NatB comple
Electron Microscopy Public Image Archive, 10477.

https://www.ebi.ac.uk/pdbe/emdb/empiar/entry/10477/

Article and author information

Author details

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.

"This ORCID iD identifies the author of this article:" 0000-0001-7798-4317
Buyan Pan

Chemistry, University of Pennsylvania, Philadelphia, United States

Competing interests
The authors declare that no competing interests exist.
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.
James Petersson

Chemistry, University of Pennsylvania, Philadelphia, United States

Competing interests
The authors declare that no competing interests exist.
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.

"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.

Copyright

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.