Most mutations that cause spinocerebellar ataxia autosomal recessive type 16 (SCAR16) destabilize the protein quality-control E3 ligase CHIP
| Autor: | Oliver J. Newsom, Kenneth Matthew Scaglione, Adam J. Kanack |
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| Rok vydání: | 2018 |
| Předmět: |
Models
Molecular 0301 basic medicine Hot Temperature Protein Conformation Ubiquitin-Protein Ligases Mutant Mutation Missense Down-Regulation Fluorescence Polarization Protein aggregation Biochemistry 03 medical and health sciences 0302 clinical medicine Ubiquitin Enzyme Stability Fluorescence Resonance Energy Transfer medicine Humans Point Mutation Spinocerebellar Ataxias Molecular Biology biology Chemistry Limb ataxia Ubiquitination Molecular Bases of Disease Cell Biology medicine.disease Peptide Fragments Recombinant Proteins Ubiquitin ligase Cell biology HEK293 Cells 030104 developmental biology Proteostasis Amino Acid Substitution Solubility Mutation Mutagenesis Site-Directed Spinocerebellar ataxia biology.protein Protein folding 030217 neurology & neurosurgery |
| Zdroj: | Journal of Biological Chemistry. 293:2735-2743 |
| ISSN: | 0021-9258 |
| Popis: | The accumulation of misfolded proteins promotes protein aggregation and neuronal death in many neurodegenerative diseases. To counteract misfolded protein accumulation, neurons have pathways that recognize and refold or degrade aggregation-prone proteins. One U-box-containing E3 ligase, C terminus of Hsc70-interacting protein (CHIP), plays a key role in this process, targeting misfolded proteins for proteasomal degradation. CHIP plays a protective role in mouse models of neurodegenerative disease, and in humans, mutations in CHIP cause spinocerebellar ataxia autosomal recessive type 16 (SCAR16), a fatal neurodegenerative disease characterized by truncal and limb ataxia that results in gait instability. Here, we systematically analyzed CHIP mutations that cause SCAR16 and found that most SCAR16 mutations destabilize CHIP. This destabilization caused mutation-specific defects in CHIP activity, including increased formation of soluble oligomers, decreased interactions with chaperones, diminished substrate ubiquitination, and reduced steady-state levels in cells. Consistent with decreased CHIP stability promoting its dysfunction in SCAR16, most mutant proteins recovered activity when the assays were performed below the mutants' melting temperature. Together, our results have uncovered the molecular basis of genetic defects in CHIP function that cause SCAR16. Our insights suggest that compounds that improve the thermostability of genetic CHIP variants may be beneficial for treating patients with SCAR16. |
| Databáze: | OpenAIRE |
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