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Degron capability of the hydrophobic C‐terminus of the polyglutamine disease protein, ataxin‐3
Author(s) -
Blount Jessica R.,
Johnson Sean L.,
Libohova Kozeta,
Todi Sokol V.,
Tsou WeiLing
Publication year - 2020
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.24684
Subject(s) - degron , gene isoform , spinocerebellar ataxia , n terminus , microbiology and biotechnology , alternative splicing , machado–joseph disease , proteasome , biochemistry , c terminus , biology , ubiquitin , proteolysis , protein degradation , chemistry , peptide sequence , ubiquitin ligase , amino acid , gene , enzyme
Ataxin‐3 is a deubiquitinase and polyglutamine disease protein whose cellular properties and functions are not entirely understood. Mutations in ataxin‐3 cause spinocerebellar ataxia type 3 (SCA3), a neurodegenerative disorder that is a member of the polyglutamine family of diseases. Two major isoforms arise from alternative splicing of ATXN3 and are differently toxic in vivo as a result of faster proteasomal degradation of one isoform compared to the other. The isoforms vary only at their C‐termini, suggesting that the hydrophobic C‐terminus of the more quickly degraded form of ataxin‐3 (here referred to as isoform 2) functions as a degron—that is, a peptide sequence that expedites the degradation of its host protein. We explored this notion in this study and present evidence that: (a) the C‐terminus of ataxin‐3 isoform 2 signals its degradation in a proteasome‐dependent manner, (b) this effect from the C‐terminus of isoform 2 does not require the ubiquitination of ataxin‐3, and (c) the isolated C‐terminus of isoform 2 can enhance the degradation of an unrelated protein. According to our data, the C‐terminus of ataxin‐3 isoform 2 is a degron, increasing overall understanding of the cellular properties of the SCA3 protein.