Dataset Information

Unsaturated Fatty Acid-Induced Conformational Transitions and Aggregation of the Repeat Domain of Tau.

ABSTRACT:

Background

The intrinsically disordered, amyloidogenic protein Tau associates with diverse classes of molecules, including proteins, nucleic acids, and lipids. Mounting evidence suggests that fatty acid molecules could play a role in the dysfunction of this protein, however, their interaction with Tau remains poorly characterized.

Methods

In a bid to elucidate the association of Tau with unsaturated fatty acids at the sub-molecular level, we carried out a variety of solution NMR experiments in combination with circular dichroism and fluorescence measurements. Our study shows that Tau^4RD, the highly basic four-repeat domain of Tau, associates strongly with arachidonic and oleic acid assemblies in a high lipid/protein ratio, perturbing their supramolecular states and itself undergoing time-dependent structural adaptation. The structural signatures of Tau^4RD/fatty acid aggregates appear similar for arachidonic acid and oleic acid, however, they are distinct from those of another prototypical intrinsically disordered protein, ?-synuclein, when bound to these lipids, revealing protein-specific conformational adaptations. Both fatty acid molecules are found to invariably promote the self-aggregation of Tau^4RD and of ?-synuclein.

Conclusions

This study describes the reciprocal influence that Tau^4RD and fatty acids exert on their conformational states, contributing to our understanding of fundamental aspects of Tau/lipid co-assembly.

SUBMITTER: Barracchia CG

PROVIDER: S-EPMC7321374 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Publications

Unsaturated Fatty Acid-Induced Conformational Transitions and Aggregation of the Repeat Domain of Tau.

Barracchia Carlo Giorgio CG Tira Roberto R Parolini Francesca F Munari Francesca F Bubacco Luigi L Spyroulias Georgios A GA D'Onofrio Mariapina M Assfalg Michael M

Molecules (Basel, Switzerland) 20200611 11

<h4>Background</h4>The intrinsically disordered, amyloidogenic protein Tau associates with diverse classes of molecules, including proteins, nucleic acids, and lipids. Mounting evidence suggests that fatty acid molecules could play a role in the dysfunction of this protein, however, their interaction with Tau remains poorly characterized.<h4>Methods</h4>In a bid to elucidate the association of Tau with unsaturated fatty acids at the sub-molecular level, we carried out a variety of solution NMR e ...[more]

PMID: 32545360

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Project description:The large family of Gram-positive quorum-sensing receptors known as the RNPP proteins consists of receptors homologous to the Rap, NprR, PlcR, and PrgX proteins that are regulated by imported oligopeptide autoinducers. Rap proteins are phosphatases and transcriptional anti-activators, and NprR, PlcR, and PrgX proteins are DNA binding transcription factors. Despite their obvious importance, the mechanistic basis of oligopeptide receptor regulation is largely unknown. Here, we report the X-ray crystal structure of the Bacillus subtilis quorum-sensing receptor RapJ in complex with the centrally important oligopeptide autoinducer competence and sporulation factor (CSF, also termed PhrC), a member of the Phr family of quorum-sensing signals. Furthermore, we present the crystal structure of RapI. Comparison of the RapJ-PhrC, RapI, RapH-Spo0F, and RapF-ComA(C) crystal structures reveals the mechanistic basis of Phr activity. More specifically, when complexed with target proteins, Rap proteins consist of a C-terminal tetratricopeptide repeat (TPR) domain connected by a flexible helix-containing linker to an N-terminal 3-helix bundle. In the absence of a target protein or regulatory peptide, the Rap protein 3-helix bundle adopts different conformations. However, in the peptide-bound conformation, the Rap protein N-terminal 3-helix bundle and linker undergo a radical conformational change, form TPR-like folds, and merge with the existing C-terminal TPR domain. To our knowledge, this is the first example of conformational change-induced repeat domain expansion. Furthermore, upon Phr binding, the entire Rap protein is compressed along the TPR superhelical axis, generating new intramolecular contacts that lock the Rap protein in an inactive state. The fact that Rap proteins are conformationally flexible is surprising considering that it is accepted dogma that TPR proteins do not undergo large conformational changes. Repeat proteins are widely used as scaffolds for the development of designed affinity reagents, and we propose that Rap proteins could be used as scaffolds for engineering novel ligand-switchable affinity reagents.

Dataset Information

Unsaturated Fatty Acid-Induced Conformational Transitions and Aggregation of the Repeat Domain of Tau.

Background

Methods

Conclusions

Publications

Unsaturated Fatty Acid-Induced Conformational Transitions and Aggregation of the Repeat Domain of Tau.

Similar Datasets

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