Copper Binding to the N-Terminally Acetylated, Naturally Occurring Form of Alpha-Synuclein Induces Local Helical Folding

Miotto, Marco C.; Valiente-Gabioud, Ariel A.; Rossetti, Giulia; Zweckstetter, Markus; Carloni, Paolo; Selenko, Philipp; Griesinger, Christian; Binolfi, Andrés; Fernández, Claudio O.

doi:10.1021/jacs.5b01911

Cited by 71 publications

(79 citation statements)

References 40 publications

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“…Cu(I) coordination to the 1‐15 AS fragment has also been studied upon association with membranes, where the formation of 1:2 AS:Cu(I) complex has been proposed, with Cu(I) bridging between two helical peptide chains via Met residues (Dell’Acqua et al ). Most interestingly, NMR‐based studies have described that Cu(I) binding to the N‐terminal region of AS stabilizes local conformations with α‐helical secondary structure and restricted mobility (Miotto et al ), an event that might be relevant for the association of the protein to membranes and its physiological function in vesicle trafficking.…”

Section: α‐Synuclein Is a Metal‐binding Proteinmentioning

confidence: 99%

“…Since copper ions are predominantly found in their Cu(I) state in the reducing environment of living cells, characterization of the physiologically relevant Cu(I) complexes became particularly important (Binolfi et al 2011;Miotto et al 2015;Miotto et al 2017;Gentile et al 2018;Abeyawardhane et al 2018b). These studies revealed that Cu(I) binding to the high-affinity Met1-X3-Met5 site is influenced by acetylation at the N-terminus (Fig.…”

Section: Sumoylation Of A-synucleinmentioning

confidence: 99%

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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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Section: α‐Synuclein Is a Metal‐binding Proteinmentioning

confidence: 99%

Section: Sumoylation Of A-synucleinmentioning

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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“…N-terminal acetylation (NTA) is an irreversible protein modification that predominantly occurs co-translationally on eukaryotic nascent chains emerging from the ribosome exit tunnel [1]. This modification occurs on ~ 80% of human proteins [2] and impacts several protein functions including complex formation [3][4][5][6][7], protein localization [8][9][10][11][12], and the N-end rule for protein degradation [13][14][15]. NTA is catalyzed by a group of enzymes called N-terminal acetyltransferases (NATs) which belong to the Gcn5-related Nacetyltransferase (GNAT) family of enzymes.…”

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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“…[4,[21][22][23] The acetylated form of aS has the same coordination site. [24] Like aS, bS is an intrinsically disordered protein found in the presynaptic nerve terminals. bS constitutes the majority of the synuclein content in healthy brain and it has an intrinsic ability to prevent aS aggregation and oligomerisation.…”

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confidence: 99%

Copper(I/II), α/β‐Synuclein and Amyloid‐β: Menage à Trois?

et al. 2015

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Copper binding to α-synuclein (aS) and to amyloid-β (Ab) has been connected to Parkinson's and Alzheimer's disease (AD), respectively, because Cu ions can modulate the peptide aggregation, and these Cu ⋅ peptide complexes can catalyse the production of reactive oxygen species (ROS). In a significant proportion of AD brains, aggregation of aS and Ab has been detected, and it was proposed that Ab and aS interact with each other. Thus, we investigated the potential interactions of Ab and aS through their binding of copper(I) and copper(II). Additionally, β-synuclein (bS) was investigated, due to its additional methionine residue, a potential Cu(I) ligand. We found that: 1) the peptides containing the Cu-binding domains Ab1-16, aS1-15 and bS1-15 have similar affinities towards Cu(II) and towards Cu(I), with Ab1-16 being slightly stronger, 2) in the case of Cu(I), the additional Met residue in bS1-15 increased the affinity slightly, 3) the exchange of Cu(I/II) between the two peptides is rapid (≤ ms), 4) a/bS1-15 and Ab1-16 form a heterodimeric complex with Cu(II), 5) Cu(I) probably promotes a transient ternary complex, 6) the different Cu(I/II) coordination of Ab1-16, aS1-15 and bS1-15 impacts the capacity to produce ROS and to oxidise catechol, and 7) when Ab1-16, aS1-15 and Cu are present, the ROS production more closely resembles that by Ab1-16. The work gives insights into the coordination chemistry of these related peptides, and the relevance of coordination differences, the ternary complex and ROS production are discussed.

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Copper Binding to the N-Terminally Acetylated, Naturally Occurring Form of Alpha-Synuclein Induces Local Helical Folding

Cited by 71 publications

References 40 publications

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

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

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

Copper(I/II), α/β‐Synuclein and Amyloid‐β: Menage à Trois?

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