Residue Histidine 50 Plays a Key Role in Protecting α-Synuclein from Aggregation at Physiological pH

Chi, Ying-Chih; Armstrong, Geoffrey S.; Jones, David N. M.; Eisenmesser, Elan; Liu, Changwei

doi:10.1074/jbc.m113.544049

Cited by 23 publications

(27 citation statements)

References 48 publications

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“…To investigate further the causes of the increased aggregation propensity of the H50Q variant, we characterize the monomeric ensembles of both WT and H50Q α-Syn using NMR spectroscopy. In previous reports, comparative spectroscopic analyses have revealed broadly similar structural ensembles in the WT and H50Q variants, with a small number of chemical shift changes around the site of the mutation ( 18 – 20 ) and, in some cases, additional perturbations in the C-terminal region ( 18 , 19 ). Here we carry out a comprehensive chemical shift-based analysis of WT and H50Q α-Syn, using the δ2D algorithm ( 24 ) to scrutinize changes in the residual secondary structure of the variant.…”

Section: Introductionmentioning

confidence: 85%

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The H50Q Mutation Induces a 10-fold Decrease in the Solubility of α-Synuclein

Porcari

Proukakis

Waudby

et al. 2015

Journal of Biological Chemistry

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Background: The basis of the pathogenicity of the H50Q variant α-synuclein is unknown.Results: The critical concentration of α-synuclein is decreased by 10-fold by the H50Q mutation, and its aggregation is modulated by the wild-type isoform.Conclusion: Key effects of the H50Q mutation on the aggregation of α-synuclein can be quantified.Significance: Our data provide insights into the mechanism of Lewy body formation in vivo.

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Section: Introductionmentioning

confidence: 85%

“…The recently identified H50Q α-Syn mutation ( 16 , 17 ) was shown to aggregate faster in vitro compared with the WT counterpart ( 18 – 21 ). Here we compare sequence-based predictions of aggregation propensity ( 22 , 23 ) with further experimental observations of aggregation behavior in the WT and H50Q α-Syn.…”

Section: Introductionmentioning

confidence: 98%

The H50Q Mutation Induces a 10-fold Decrease in the Solubility of α-Synuclein

Porcari

Proukakis

Waudby

et al. 2015

Journal of Biological Chemistry

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“…In contrast, however, interactions between ␣-synuclein and CsgC were found to prevent amyloid polymerization (6). The authors suggested that interactions between CsgC and ␣-synuclein enhanced intraprotein interactions, shielding NAC from exposure and thus preventing fibrillization of ␣-synuclein (135). Furthermore, Westermark and colleges showed that curli fibers enhance the fibrillization of amyloid protein A, which is implicated in the pathogenesis of systemic amyloidosis (136).…”

Section: Enteric Biofilm Amyloids and Neurodegenerative Diseasesmentioning

confidence: 99%

Curli-Containing Enteric Biofilms Inside and Out: Matrix Composition, Immune Recognition, and Disease Implications

Tursi

Tükel

2018

Microbiol Mol Biol Rev

124

110

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SUMMARYBiofilms of enteric bacteria are highly complex, with multiple components that interact to fortify the biofilm matrix. Within biofilms of enteric bacteria such asEscherichia coliandSalmonellaspecies, the main component of the biofilm is amyloid curli. Other constituents include cellulose, extracellular DNA, O antigen, and various surface proteins, including BapA. Only recently, the roles of these components in the formation of the enteric biofilm individually and in consortium have been evaluated. In addition to enhancing the stability and strength of the matrix, the components of the enteric biofilm influence bacterial virulence and transmission. Most notably, certain components of the matrix are recognized as pathogen-associated molecular patterns. Systemic recognition of enteric biofilms leads to the activation of several proinflammatory innate immune receptors, including the Toll-like receptor 2 (TLR2)/TLR1/CD14 heterocomplex, TLR9, and NLRP3. In the model ofSalmonella entericaserovar Typhimurium, the immune response to curli is site specific. Although a proinflammatory response is generated upon systemic presentation of curli, oral administration of curli ameliorates the damaged intestinal epithelial barrier and reduces the severity of colitis. Furthermore, curli (and extracellular DNA) of enteric biofilms potentiate the autoimmune disease systemic lupus erythematosus (SLE) and promote the fibrillization of the pathogenic amyloid α-synuclein, which is implicated in Parkinson's disease. Homologues of curli-encoding genes are found in four additional bacterial phyla, suggesting that the biomedical implications involved with enteric biofilms are applicable to numerous bacterial species.

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“…[1][2][3][4][5] In PD these intraneuronal proteinaceous inclusion bodies, referred to as Lewy bodies, are composed primarily of fibrillar and aggregated forms of wild-type and post-translationally modified a-synuclein. 1,2,6 Various mutations in the gene coding for a-synuclein (including A30P, 7 H50Q, 8,9 G51D, 10 A53T, 11 and E46K 12 ) are associated with familial forms of the disorder, although they account for only 1-5% of PD cases. 13 Understanding the role of the molecular and structural determinants of the functional and aggregation properties of a-synuclein is therefore pivotal in elucidating the role of this protein in the pathogenesis of PD, as well as identifying novel diagnostic and therapeutic strategies for the treatment of the wider family of synucleinopathies.…”

Section: Introductionmentioning

confidence: 99%

Exploring the role of post‐translational modifications in regulating α‐synuclein interactions by studying the effects of phosphorylation on nanobody binding

et al. 2018

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Intracellular deposits of α-synuclein in the form of Lewy bodies are major hallmarks of Parkinson's disease (PD) and a range of related neurodegenerative disorders. Post-translational modifications (PTMs) of α-synuclein are increasingly thought to be major modulators of its structure, function, degradation and toxicity. Among these PTMs, phosphorylation near the C-terminus at S129 has emerged as a dominant pathogenic modification as it is consistently observed to occur within the brain and cerebrospinal fluid (CSF) of post-mortem PD patients, and its level appears to correlate with disease progression. Phosphorylation at the neighboring tyrosine residue Y125 has also been shown to protect against α-synuclein toxicity in a Drosophila model of PD. In the present study we address the potential roles of C-terminal phosphorylation in modulating the interaction of α-synuclein with other protein partners, using a single domain antibody fragment (NbSyn87) that binds to the C-terminal region of α-synuclein with nanomolar affinity. The results reveal that phosphorylation at S129 has negligible effect on the binding affinity of NbSyn87 to α-synuclein while phosphorylation at Y125, only four residues away, decreases the binding affinity by a factor of 400. These findings show that, despite the fact that α-synuclein is intrinsically disordered in solution, selective phosphorylation can modulate significantly its interactions with other molecules and suggest how this particular form of modification could play a key role in regulating the normal and aberrant function of α-synuclein.

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Residue Histidine 50 Plays a Key Role in Protecting α-Synuclein from Aggregation at Physiological pH

Cited by 23 publications

References 48 publications

The H50Q Mutation Induces a 10-fold Decrease in the Solubility of α-Synuclein

The H50Q Mutation Induces a 10-fold Decrease in the Solubility of α-Synuclein

Curli-Containing Enteric Biofilms Inside and Out: Matrix Composition, Immune Recognition, and Disease Implications

Exploring the role of post‐translational modifications in regulating α‐synuclein interactions by studying the effects of phosphorylation on nanobody binding

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