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A Single Reactive Noncanonical Amino Acid Is Able to Dramatically Stabilize Protein Structure.

ABSTRACT: A p-isothiocyanate phenylalanine mutant of the homodimeric protein homoserine o-succinyltransferase (MetA) was isolated in a temperature dependent selection from a library of metA mutants containing noncanonical amino acids. This mutant protein has a dramatic increase of 24 °C in thermal stability compared to the wild type protein. Peptide mapping experiments revealed that the isothiocyanate group forms a thiourea cross-link to the N terminal proline of the other monomer, despite the two positions being >30 Å apart in the X-ray crystal structure of the wild type protein. These results show that an expanded set of building blocks beyond the canonical 20 amino acids can lead to significant changes in the properties of proteins.

SUBMITTER: Li JC

PROVIDER: S-EPMC6791372 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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A Single Reactive Noncanonical Amino Acid Is Able to Dramatically Stabilize Protein Structure.

Li Jack C JC Nastertorabi Fariborz F Xuan Weimin W Han Gye Won GW Stevens Raymond C RC Schultz Peter G PG

ACS chemical biology 20190604 6

A p-isothiocyanate phenylalanine mutant of the homodimeric protein homoserine o-succinyltransferase (MetA) was isolated in a temperature dependent selection from a library of metA mutants containing noncanonical amino acids. This mutant protein has a dramatic increase of 24 °C in thermal stability compared to the wild type protein. Peptide mapping experiments revealed that the isothiocyanate group forms a thiourea cross-link to the N terminal proline of the other monomer, despite the two positio ...[more]

PMID: 31181898

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Project description:BackgroundGenomic variations may cause deleterious effects on protein functionality and perturb biological processes. Elucidating the effects of variations is critical for developing novel treatment strategies for diseases of genetic origin. Computational approaches have been aiding the work in this field by modeling and analyzing the mutational landscape. However, new approaches are required, especially for accurate representation and data-centric analysis of sequence variations.MethodIn this study, we propose ASCARIS (Annotation and StruCture-bAsed RepresentatIon of Single amino acid variations), a method for the featurization (i.e., quantitative representation) of single amino acid variations (SAVs), which could be used for a variety of purposes, such as predicting their functional effects or building multi-omics-based integrative models. ASCARIS utilizes the direct and spatial correspondence between the location of the SAV on the sequence/structure and 30 different types of positional feature annotations (e.g., active/lipidation/glycosylation sites; calcium/metal/DNA binding, inter/transmembrane regions, etc.), along with structural features and physicochemical properties. The main novelty of this method lies in constructing reusable numerical representations of SAVs via functional annotations.ResultsWe statistically analyzed the relationship between these features and the consequences of variations and found that each carries information in this regard. To investigate potential applications of ASCARIS, we trained variant effect prediction models that utilize our SAV representations as input. We carried out an ablation study and a comparison against the state-of-the-art methods and observed that ASCARIS has a competing and complementary performance against widely-used predictors. ASCARIS can be used alone or in combination with other approaches to represent SAVs from a functional perspective. ASCARIS is available as a programmatic tool at https://github.com/HUBioDataLab/ASCARIS and as a web-service at https://huggingface.co/spaces/HUBioDataLab/ASCARIS.

Dataset Information

A Single Reactive Noncanonical Amino Acid Is Able to Dramatically Stabilize Protein Structure.

Publications

A Single Reactive Noncanonical Amino Acid Is Able to Dramatically Stabilize Protein Structure.

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