Mapping Interactions with the Chaperone Network Reveals Factors that Protect Against Tau Aggregation
| Autor: | Bryan M. Dunyak, Jungsoon Lee, Mark R. Wilson, Harindranath Kadavath, Victoria A. Assimon, Francis T.F. Tsai, Olivier Julien, Chad A. Dickey, Jennifer N. Rauch, Markus Zweckstetter, Rebecca Freilich, Sue-Ann Mok, Anne T. Gillies, Jason E. Gestwicki, Carlo Condello, Javier Oroz, Taylor Arhar |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Aging Regulator protein-protein interactions Neurodegenerative Alzheimer's Disease Medical and Health Sciences Biochemistry purified proteins metabolism [HSP40 Heat-Shock Proteins] 0302 clinical medicine Structural Biology protein folding 2.1 Biological and endogenous factors Aetiology biology Brain Biological Sciences Protein folding physiology [Protein Binding] Protein Binding Tau pathology Tau protein Biophysics MAPT protein human tau Proteins Computational biology DNAJA2 protein human Protein Aggregation Pathological prevention & control [Protein Aggregation Pathological] Article protein aggregation 03 medical and health sciences Protein Aggregates Pathological ddc:570 mental disorders Acquired Cognitive Impairment Humans physiology [Protein Aggregates] protein quality control Molecular Biology tauopathy Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) HSP40 Heat-Shock Proteins Protein Aggregation metabolism [tau Proteins] Brain Disorders 030104 developmental biology metabolism [Brain] Chaperone (protein) Chemical Sciences heat shock proteins biology.protein Proteostasis Dementia 030217 neurology & neurosurgery Developmental Biology Neuroscience |
| Zdroj: | Nature structural & molecular biology Nature Structural and Molecular Biology Nature structural & molecular biology 25(5), 384-393 (2018). doi:10.1038/s41594-018-0057-1 Nature structural & molecular biology, vol 25, iss 5 |
| ISSN: | 1545-9985 1545-9993 |
| Popis: | A network of molecular chaperones is known to bind proteins (“clients”) and balance their folding, function and turnover. However, it is often not clear which chaperones are critical for selective recognition of individual clients. It is also not clear why these key chaperones might fail in protein aggregation diseases. In this study, we utilized human microtubule-associated protein tau (MAPT or tau) as a model client to survey interactions between ~30 purified chaperones and ~20 disease-associated tau variants (~600 combinations). From this large-scale analysis, we identified human DnaJA2 as an unexpected, but potent, inhibitor of tau aggregation. DnaJA2 levels were correlated with tau pathology in human brains, supporting the idea that it is an important regulator of tau homeostasis. Of significance, we found that some disease-associated tau variants were relatively immune to interactions with chaperones, suggesting a model in which avoiding physical recognition by chaperone networks may contribute to disease. Impact Statement Large-scale screening of chaperone interactions with tau and its variants identified DnaJA2 as a key protective factor in tauopathy. |
| Databáze: | OpenAIRE |
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