Competing Interactions Stabilize Pro- and Anti-aggregant Conformations of Human Tau
| Autor: | Christian A. Bippes, Susanne Wegmann, Daniel J. Müller, Jonas Schöler, Eckhard Mandelkow |
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| Rok vydání: | 2011 |
| Předmět: |
Protein Folding
Mutant genetics [Alzheimer Disease] MAPT protein human tau Proteins Fibril Biochemistry Protein structure Neurobiology Alzheimer Disease medicine Humans Protein Structure Quaternary genetics [Frontotemporal Dementia] Molecular Biology chemistry.chemical_classification Chemistry chemistry [tau Proteins] Neurodegeneration Cell Biology medicine.disease metabolism [tau Proteins] Protein Structure Tertiary Amino acid N-terminus genetics [tau Proteins] Frontotemporal Dementia Intramolecular force ddc:540 metabolism [Frontotemporal Dementia] Mutation Biophysics Protein folding metabolism [Alzheimer Disease] |
| Zdroj: | The journal of biological chemistry 286(23), 20512-20524 (2011). doi:10.1074/jbc.M111.237875 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m111.237875 |
| Popis: | Aggregation of Tau into amyloid-like fibrils is a key process in neurodegenerative diseases such as Alzheimer. To understand how natively disordered Tau stabilizes conformations that favor pathological aggregation, we applied single-molecule force spectroscopy. Intramolecular interactions that fold polypeptide stretches of ∼19 and ∼42 amino acids in the functionally important repeat domain of full-length human Tau (hTau40) support aggregation. In contrast, the unstructured N terminus randomly folds long polypeptide stretches >100 amino acids that prevent aggregation. The pro-aggregant mutant hTau40ΔK280 observed in frontotemporal dementia favored the folding of short polypeptide stretches and suppressed the folding of long ones. This trend was reversed in the anti-aggregant mutant hTau40ΔK280/PP. The aggregation inducer heparin introduced strong interactions in hTau40 and hTau40ΔK280 that stabilized aggregation-prone conformations. We show that the conformation and aggregation of Tau are regulated through a complex balance of different intra- and intermolecular interactions. |
| Databáze: | OpenAIRE |
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