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Effect of Post-Translational Modifications and Mutations on Amyloid-? Fibrils Dynamics at N Terminus.

ABSTRACT: We investigate the variability in the dynamics of the disordered N-terminal domain of amyloid-? fibrils (A?), comprising residues 1-16 of A?1-40, due to post-translational modifications and mutations in the ?-bend regions known to modulate aggregation properties. Using 2H static solid-state NMR approaches, we compare the dynamics in the wild-type A? fibrils in the threefold symmetric polymorph with the fibrils from three post-translational modification sequences: isoaspartate-D7, the phosphorylation of S8, and an N-terminal truncation ?E3. Additional comparisons are made with the mutants in the ?-bend region (residues 21-23) corresponding to the familial Osaka E22? deletion and D23N Iowa mutation. We also include the aggregates induced by Zn2+ ions. The dynamics are probed at the F4 and G9 positions. The main motional model involves two free states undergoing diffusion and conformational exchanges with the bound state in which the diffusion is quenched because of transient interactions involving fibril core and other intrastrand contacts. The fraction of the bound state increases in a sigmoidal fashion with a decrease in temperature. There is clear variability in the dynamics: the phosphorylation of S8 variant is the most rigid at the G9 site in line with structural studies, the ?E3 fibrils are more flexible at the G9 site in line with the morphological fragmentation pattern, the Zn-induced aggregates are the most mobile, and the two ?-bend mutants have the strongest changes at the F4 site toward higher rigidity. Overall, the changes underlie the potential role of conformational ensembles in setting the stage for aggregation-prone states.

SUBMITTER: Vugmeyster L

PROVIDER: S-EPMC6817547 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Effect of Post-Translational Modifications and Mutations on Amyloid-β Fibrils Dynamics at N Terminus.

Vugmeyster Liliya L Au Dan F DF Ostrovsky Dmitry D Kierl Brian B Fu Riqiang R Hu Zhi-Wen ZW Qiang Wei W

Biophysical journal 20190912 8

We investigate the variability in the dynamics of the disordered N-terminal domain of amyloid-β fibrils (Aβ), comprising residues 1-16 of Aβ<sub>1-40</sub>, due to post-translational modifications and mutations in the β-bend regions known to modulate aggregation properties. Using <sup>2</sup>H static solid-state NMR approaches, we compare the dynamics in the wild-type Aβ fibrils in the threefold symmetric polymorph with the fibrils from three post-translational modification sequences: isoasparta ...[more]

PMID: 31570231

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Project description:BACKGROUND:Protein post-translational modifications (PTMs) are an important aspect of protein regulation. The number of PTMs discovered within the human proteome, and other proteomes, has been rapidly expanding in recent years. As a consequence of the rate in which new PTMs are identified, analysis done in one year may result in different conclusions when repeated in subsequent years. Among the various functional questions pertaining to PTMs, one important relationship to address is the interplay between modifications and mutations. Specifically, because the linear sequence surrounding a modification site often determines molecular recognition, it is hypothesized that mutations near sites of PTMs may be more likely to result in a detrimental effect on protein function, resulting in the development of disease. METHODS AND RESULTS:We wrote an application programming interface (API) to make analysis of ProteomeScout, a comprehensive database of PTMs and protein information, easy and reproducible. We used this API to analyze the relationship between PTMs and human mutations associated with disease (based on the 'Clinical Significance' annotation from dbSNP). Proteins containing pathogenic mutations demonstrated a significant study bias which was controlled for by analyzing only well-studied proteins, based on their having at least one pathogenic mutation. We found that pathogenic mutations are significantly more likely to lie within eight amino acids of a phosphoserine, phosphotyrosine or ubiquitination site when compared to mutations in general, based on a Fisher's Exact test. Despite the skew of pathogenic mutations occurring on positively charged arginines, we could not account for this relationship based only on residue type. Finally, we hypothesize a potential mechanism for a pathogenic mutation on RAF1, based on its proximity to a phosphorylation site, which represents a subtle regulation difference that may explain why its biochemical effect has failed to be uncovered previously. The combination of the API and a dynamically expanding PTM database will make the reanalysis of this question and other systems-level questions easier in the future.

Dataset Information

Effect of Post-Translational Modifications and Mutations on Amyloid-? Fibrils Dynamics at N Terminus.

Publications

Effect of Post-Translational Modifications and Mutations on Amyloid-β Fibrils Dynamics at N Terminus.

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