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bioRxiv · 10.1101/2020.05.11.089318

Molecular Basis for N-terminal Alpha-Synuclein Acetylation by Human NatB

Marmorstein, R.·Deng, S.·Pan, B.·Gottlieb, L.·Petersson, J.
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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 -synuclein (Syn). Human NatB (hNatB) mediated N-terminal acetylation of Syn has been demonstrated to play key roles in Parkinsons disease pathogenesis and as a potential therapeutic target for hepatocellular carcinoma. Here we report the cryo-EM structure of hNatB bound to a CoA-Syn 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 Syn 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.

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Marmorstein, R., Deng, S., Pan, B., Gottlieb, L., Petersson, J.. 2020-05-13. Molecular Basis for N-terminal Alpha-Synuclein Acetylation by Human NatB. https://doi.org/10.1101/2020.05.11.089318

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