Direct observation of the three regions in α-synuclein that determine its membrane-bound behaviour

Fusco, Giuliana; Simone, Alfonso De; Gopinath, T.; Vostrikov, Vitaly V.; Vendruscolo, Michele; Dobson, Christopher M.; Veglia, Gianluigi

doi:10.1038/ncomms4827

Cited by 382 publications

(597 citation statements)

References 54 publications

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“…In this structure, the N-terminal region is composed of two ␣-helices consisting of residues 3-37 and 45-92. The first helical region, known to be most important for membrane binding (34,40,(57)(58)(59), is embedded in the membrane in the model, whereas the second helix is positioned above the membrane and in contact with GCase (Fig. 6A, Exposed model).…”

Section: Discussionmentioning

confidence: 99%

Structural Features of Membrane-bound Glucocerebrosidase and α-Synuclein Probed by Neutron Reflectometry and Fluorescence Spectroscopy

Yap¹,

Jiang²,

Heinrich

et al. 2015

Journal of Biological Chemistry

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Background: A specific interaction exists between ␣-synuclein and glucocerebrosidase on the lipid membrane, resulting in enzyme inhibition. Results: Binding glucocerebrosidase has a profound effect on ␣-synuclein, moving roughly half of its embedded helical region above the membrane plane. Conclusion: A model is proposed with structural insights into glucocerebrosidase inhibition by ␣-synuclein. Significance: ␣-Synuclein-glucocerebrosidase interaction provides a molecular connection between Parkinson and Gaucher diseases.

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Section: Discussionmentioning

confidence: 99%

Structural Features of Membrane-bound Glucocerebrosidase and α-Synuclein Probed by Neutron Reflectometry and Fluorescence Spectroscopy

Yap¹,

Jiang²,

Heinrich

et al. 2015

Journal of Biological Chemistry

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“…For instance, in the N-terminal membrane-binding site of α-synuclein, two familial mutations (Ala30Pro and Glu46Lys) have been hypothesized to alter membrane binding by changing the population of its conformational ensemble (51,52).…”

Section: Structural Determinants Of the C-ring1b/nupr1 Interaction Inmentioning

confidence: 99%

Intrinsically disordered chromatin protein NUPR1 binds to the C-terminal region of Polycomb RING1B

Santofimia‐Castaño

Rizzuti

Pey

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Intrinsically disordered proteins (IDPs) are ubiquitous in eukaryotes, and they are often associated with diseases in humans. The protein NUPR1 is a multifunctional IDP involved in chromatin remodeling and in the development and progression of pancreatic cancer; however, the details of such functions are unknown. Polycomb proteins are involved in specific transcriptional cascades and gene silencing. One of the proteins of the Polycomb complex is the Ring finger protein 1 (RING1). RING1 is related to aggressive tumor features in multiple cancer types. In this work we characterized the interaction between NUPR1 and the paralogue RING1B in vitro, in silico, and in cellulo. The interaction occurred through the C-terminal region of RING1B (C-RING1B), with an affinity in the low micromolar range (∼10 μM). The binding region of NUPR1, mapped by NMR, was a hydrophobic polypeptide patch at the 30s region of its sequence, as pinpointed by computational results and site-directed mutagenesis at Ala33. The association between C-RING1B and wild-type NUPR1 also occurred in cellulo as tested by protein ligation assays; this interaction is inhibited by trifluoperazine, a drug known to hamper binding of wild-type NUPR1 with other proteins. Furthermore, the Thr68Gln and Ala33Gln/Thr68Gln mutants had a reduction in the binding toward C-RING1B as shown by in vitro, in silico, and in cellulo studies. This is an example of a well-folded partner of NUPR1, because its other interacting proteins are also unfolded. We hypothesize that NUPR1 plays an active role in chromatin remodeling and carcinogenesis, together with Polycomb proteins.G ene expression control occurs through the combined activities of transcription factors and chromatin regulators, considered as effectors of epigenetic mechanisms. Posttranslational modifications of nucleosomal histones, DNA methylation, local compaction, and long-range interactions determine a variety of chromatin structures that can affect the transcriptional output.A group of chromatin regulators are the Polycomb Repressive complexes (PRCs) (1, 2). These Polycomb group (PcG) proteins are encoded by genes initially discovered over 60 years ago as repressors of the Hox genes in Drosophila (3). The PcG proteins form two main silencing heteromeric complexes called PRC1 and PRC2; both are highly conserved in eukaryotes and either in isolation or synergistically can silence genes (4, 5). The catalytic functions of both complexes include ubiquitin-ligase (H3K119ub1) and methyltransferase activity (H3K27Me3), respectively. In mammals, the PRC2 core is formed by, at least, four heteromeric units, one of which is EZH2 (or its paralog, EZH1), the methyltransferase that catalyzes the trimethylation of histone H3 at Lys27 (5). This modification can act as an anchoring site of PRC1 complexes containing chromobox (CBX) proteins. These CBX proteins recruit PRC1 complex onto PRC2-enriched chromatin, facilitating the monoubiquitylation. The PRC1-dependent monoubiquitylation at Lys119 of histone H2A correlates with transc...

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“…2A and S2). The assignment of the 13 C-13 C-DARR peaks was performed using an approach (23)(24)(25) that combines information from solution-state chemical exchange saturation transfer (23,26,27) (CEST, see Methods and Fig. S3) with known assignments of fibrillar (5) and monomeric (25) states of αS.…”

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confidence: 99%

Structural basis of membrane disruption and cellular toxicity by α-synuclein oligomers

Fusco

Chen

Williamson

et al. 2017

Science

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One Sentence Summary: Oligomers of α-synuclein generate neuronal damage when insertion of a highly structured core causes disruption of membrane integrity. This manuscript has been accepted for publication in Science. This version has not undergone final editing. Please refer to the complete version of record at http://www.sciencemag.org/. The manuscript may not be reproduced or used in any manner that does not fall within the fair use provisions of the Copyright Act without the prior, written permission of AAASAbstract: Oligomeric species populated during the aggregation process of α-synuclein have been linked to neuronal impairment in Parkinson's disease and related neurodegenerative disorders. By using solution and solid-state NMR techniques in conjunction with other structural methods, we identified the fundamental characteristics that enable toxic α-synuclein oligomers to perturb biological membranes and disrupt cellular function; these include a highly lipophilic element that promotes strong membrane interactions and a structured region that inserts into lipid bilayers and disrupts their integrity. In support of these conclusions, mutations that target the region that promotes strong membrane interactions by α-synuclein oligomers suppressed their toxicity in neuroblastoma cells and in primary cortical neurons.

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Direct observation of the three regions in α-synuclein that determine its membrane-bound behaviour

Cited by 382 publications

References 54 publications

Structural Features of Membrane-bound Glucocerebrosidase and α-Synuclein Probed by Neutron Reflectometry and Fluorescence Spectroscopy

Structural Features of Membrane-bound Glucocerebrosidase and α-Synuclein Probed by Neutron Reflectometry and Fluorescence Spectroscopy

Intrinsically disordered chromatin protein NUPR1 binds to the C-terminal region of Polycomb RING1B

Structural basis of membrane disruption and cellular toxicity by α-synuclein oligomers

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