Most mutations that cause spinocerebellar ataxia autosomal recessive type 16 (SCAR16) destabilize the protein quality-control E3 ligase CHIP.
Saved in:
| Title: | Most mutations that cause spinocerebellar ataxia autosomal recessive type 16 (SCAR16) destabilize the protein quality-control E3 ligase CHIP. |
|---|---|
| Authors: | Kanack, Adam J.1, Newsom, Oliver J.1, Scaglione, Kenneth Matthew1 mscaglione@mcw.edu |
| Source: | Journal of Biological Chemistry. 2/23/2018, Vol. 293 Issue 8, p2735-2743. 9p. |
| Subjects: | Spinocerebellar ataxia, Neurodegeneration, Proteins, Mutant proteins, Therapeutics |
| Abstract: | 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. [ABSTRACT FROM AUTHOR] |
| Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) | |
| Database: | Engineering Source |
| FullText | Text: Availability: 0 |
|---|---|
| Header | DbId: egs DbLabel: Engineering Source An: 128230161 AccessLevel: 6 PubType: Academic Journal PubTypeId: academicJournal PreciseRelevancyScore: 0 |
| IllustrationInfo | |
| Items | – Name: Title Label: Title Group: Ti Data: Most mutations that cause spinocerebellar ataxia autosomal recessive type 16 (SCAR16) destabilize the protein quality-control E3 ligase CHIP. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Kanack%2C+Adam+J%2E%22">Kanack, Adam J.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Newsom%2C+Oliver+J%2E%22">Newsom, Oliver J.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Scaglione%2C+Kenneth+Matthew%22">Scaglione, Kenneth Matthew</searchLink><relatesTo>1</relatesTo><i> mscaglione@mcw.edu</i> – Name: TitleSource Label: Source Group: Src Data: <searchLink fieldCode="JN" term="%22Journal+of+Biological+Chemistry%22">Journal of Biological Chemistry</searchLink>. 2/23/2018, Vol. 293 Issue 8, p2735-2743. 9p. – Name: Subject Label: Subjects Group: Su Data: <searchLink fieldCode="DE" term="%22Spinocerebellar+ataxia%22">Spinocerebellar ataxia</searchLink><br /><searchLink fieldCode="DE" term="%22Neurodegeneration%22">Neurodegeneration</searchLink><br /><searchLink fieldCode="DE" term="%22Proteins%22">Proteins</searchLink><br /><searchLink fieldCode="DE" term="%22Mutant+proteins%22">Mutant proteins</searchLink><br /><searchLink fieldCode="DE" term="%22Therapeutics%22">Therapeutics</searchLink> – Name: Abstract Label: Abstract Group: Ab Data: 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. [ABSTRACT FROM AUTHOR] – Name: AbstractSuppliedCopyright Label: Group: Ab Data: <i>Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.) |
| PLink | https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=egs&AN=128230161 |
| RecordInfo | BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.1074/jbc.RA117.000477 Languages: – Code: eng Text: English PhysicalDescription: Pagination: PageCount: 9 StartPage: 2735 Subjects: – SubjectFull: Spinocerebellar ataxia Type: general – SubjectFull: Neurodegeneration Type: general – SubjectFull: Proteins Type: general – SubjectFull: Mutant proteins Type: general – SubjectFull: Therapeutics Type: general Titles: – TitleFull: Most mutations that cause spinocerebellar ataxia autosomal recessive type 16 (SCAR16) destabilize the protein quality-control E3 ligase CHIP. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Kanack, Adam J. – PersonEntity: Name: NameFull: Newsom, Oliver J. – PersonEntity: Name: NameFull: Scaglione, Kenneth Matthew IsPartOfRelationships: – BibEntity: Dates: – D: 23 M: 02 Text: 2/23/2018 Type: published Y: 2018 Identifiers: – Type: issn-print Value: 00219258 Numbering: – Type: volume Value: 293 – Type: issue Value: 8 Titles: – TitleFull: Journal of Biological Chemistry Type: main |
| ResultId | 1 |
