DAXX represents a new type of protein-folding enabler
| Autor: | Guixin Zhu, Ronen Marmorstein, Xiaolu Yang, Liming Tao, JiaBei Lin, Trisha Agrawal, Sixiang Yu, Liangqian Huang, James Shorter |
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| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular Protein Folding Protein Conformation Cells Protein domain Protein aggregation Protein Aggregation Pathological Cell Line Evolution Molecular Protein Aggregates Protein structure Death-associated protein 6 Protein Domains Animals Humans Proteostasis Deficiencies Protein Unfolding Multidisciplinary biology Chemistry Proto-Oncogene Proteins c-mdm2 Cell biology Chaperone (protein) Mutation biology.protein Unfolded protein response Protein folding Tumor Suppressor Protein p53 Co-Repressor Proteins Function (biology) Molecular Chaperones |
| Zdroj: | Nature. 597:132-137 |
| ISSN: | 1476-4687 0028-0836 |
| Popis: | Protein quality control systems are crucial for cellular function and organismal health. At present, most known protein quality control systems are multicomponent machineries that operate via ATP-regulated interactions with non-native proteins to prevent aggregation and promote folding1, and few systems that can broadly enable protein folding by a different mechanism have been identified. Moreover, proteins that contain the extensively charged poly-Asp/Glu (polyD/E) region are common in eukaryotic proteomes2, but their biochemical activities remain undefined. Here we show that DAXX, a polyD/E protein that has been implicated in diverse cellular processes3–10, possesses several protein-folding activities. DAXX prevents aggregation, solubilizes pre-existing aggregates and unfolds misfolded species of model substrates and neurodegeneration-associated proteins. Notably, DAXX effectively prevents and reverses aggregation of its in vivo-validated client proteins, the tumour suppressor p53 and its principal antagonist MDM2. DAXX can also restore native conformation and function to tumour-associated, aggregation-prone p53 mutants, reducing their oncogenic properties. These DAXX activities are ATP-independent and instead rely on the polyD/E region. Other polyD/E proteins, including ANP32A and SET, can also function as stand-alone, ATP-independent molecular chaperones, disaggregases and unfoldases. Thus, polyD/E proteins probably constitute a multifunctional protein quality control system that operates via a distinctive mechanism. A protein chaperone system is identified that consists of proteins with poly-Asp/Glu sequence, and may have an important role in diseases characterized by protein aggregation. |
| Databáze: | OpenAIRE |
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