Copper Binding and Subsequent Aggregation of α-Synuclein Are Modulated by N-Terminal Acetylation and Ablated by the H50Q Missense Mutation

Mason, Rebecca J.; Paskins, Aimee R.; Dalton, Caroline; Smith, David P.

doi:10.1021/acs.biochem.6b00708

Cited by 43 publications

(65 citation statements)

References 44 publications

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“…hNatB mediates N-terminal acetylation of specific proteins, which are recognized by specific amino acid sequence at the N-terminus. There is an increasing number of proteins that depend on their N-terminal acetyl group for proper functioning [27], including NatB substrates [28, 29]. Here, we show that hNatB is upregulated in a substantial proportion of HCC tumors and that this occurs in association with microscopic vascular invasion.…”

Section: Discussionmentioning

confidence: 61%

NatB-mediated protein N-α-terminal acetylation is a potential therapeutic target in hepatocellular carcinoma

et al. 2017

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The identification of new targets for systemic therapy of hepatocellular carcinoma (HCC) is an urgent medical need. Recently, we showed that hNatB catalyzes the N-α-terminal acetylation of 15% of the human proteome and that this action is necessary for proper actin cytoskeleton structure and function. In tumors, cytoskeletal changes influence motility, invasion, survival, cell growth and tumor progression, making the cytoskeleton a very attractive antitumor target. Here, we show that hNatB subunits are upregulated in in over 59% HCC tumors compared to non-tumor tissue and that this upregulation is associated with microscopic vascular invasion. We found that hNatB silencing blocks proliferation and tumor formation in HCC cell lines in association with hampered DNA synthesis and impaired progression through the S and the G2/M phases. Growth inhibition is mediated by the degradation of two hNatB substrates, tropomyosin and CDK2, which occurs when these proteins lack N-α-terminal acetylation. In addition, hNatB inhibition disrupts the actin cytoskeleton, focal adhesions and tight/adherens junctions, abrogating two proliferative signaling pathways, Hippo/YAP and ERK1/2. Therefore, inhibition of NatB activity represents an interesting new approach to treating HCC by blocking cell proliferation and disrupting actin cytoskeleton function.

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Section: Discussionmentioning

confidence: 61%

NatB-mediated protein N-α-terminal acetylation is a potential therapeutic target in hepatocellular carcinoma

et al. 2017

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“…Consistently, N‐terminal acetylation of AS abolishes Cu(II) binding at the high‐affinity Met1 site (site 1) present in the non‐acetylated protein, but maintains low‐affinity binding with the His50 (site 2) and Asp121 (site 3) (Fig. ) (Moriarty et al, ; Mason et al ). In other words, N‐terminal acetylation abolishes the relevance of the high‐affinity site 1 for Cu(II) in AS and preserves the binding at sites 2 and 3.…”

Section: Linking Post‐translational Modifications and Metal‐binding Imentioning

confidence: 82%

“…According to this study, this interaction leads to the formation of shortened, β‐sheet enriched fibrils (< 0.2 μM) that are rapidly transmitted and accumulated to neuronal cells, causing neuronal cell death, in sharp contrast to typical AS fibrils (ca 1 μM). Interestingly, formation of these pathogenic fibrils were not observed for the AcAS‐Cu(II) interaction (Moriarty et al ; Mason et al ). Overall, these evidences indicate that N‐terminal acetylation of AS alters the binding preferences of Cu(II) by redirecting metal binding from site 1 to sites 2 and 3, affecting the morphological and conformational features of the AS amyloid fibrils induced by Cu(II) and its associated neurotoxicity.…”

Section: Linking Post‐translational Modifications and Metal‐binding Imentioning

confidence: 99%

Effects of alpha‐synuclein post‐translational modifications on metal binding

González

Arcos-López

König

et al. 2019

Journal of Neurochemistry

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Parkinson’s disease is the second most common neurodegenerative disorder worldwide. Neurodegeneration in this pathology is characterized by the loss of dopaminergic neurons in the substantia nigra, coupled with cytoplasmic inclusions known as Lewy bodies containing α‐synuclein. The brain is an organ that concentrates metal ions, and there is emerging evidence that a break‐down in metal homeostasis may be a critical factor in a variety of neurodegenerative diseases. α‐synuclein has emerged as an important metal‐binding protein in the brain, whereas these interactions play an important role in its aggregation and might represent a link between protein aggregation, oxidative damage, and neuronal cell loss. Additionally, α‐synuclein undergoes several post‐translational modifications that regulate its structure and physiological function, and may be linked to the aggregation and/or oligomer formation. This review is focused on the interaction of this protein with physiologically relevant metal ions, highlighting the cases where metal‐AS interactions profile as key modulators for its structural, aggregation, and membrane‐binding properties. The impact of α‐synuclein phosphorylation and N‐terminal acetylation in the metal‐binding properties of the protein are also discussed, underscoring a potential interplay between PTMs and metal ion binding in regulating α‐synuclein physiological functions and its role in pathology. This article is part of the Special Issue “Synuclein”.

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“…In addition, hNatB is upregulated in human hepatocellular carcinoma [43], where it has been suggested as a potential therapeutic target as silencing of this complex can block cell proliferation and tumor formation [45]. hNatB-mediated NTA of αsynuclein (αSyn) has been shown to increase αSyn stability and lipid binding, and to reduce aggregation capacity [10,[46][47][48][49][50][51][52][53]. Since αSyn is a key protein in Parkinson's disease (PD) [54,55], hNatB might play an indirect role in PD pathogenesis in vivo as supported by a recent study [56].…”

Section: Introductionmentioning

confidence: 99%

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

Marmorstein

Deng

Pan

et al. 2020

Preprint

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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 αsynuclein (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 Nterminal 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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Copper Binding and Subsequent Aggregation of α-Synuclein Are Modulated by N-Terminal Acetylation and Ablated by the H50Q Missense Mutation

Cited by 43 publications

References 44 publications

NatB-mediated protein N-α-terminal acetylation is a potential therapeutic target in hepatocellular carcinoma

NatB-mediated protein N-α-terminal acetylation is a potential therapeutic target in hepatocellular carcinoma

Effects of alpha‐synuclein post‐translational modifications on metal binding

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

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