Ataxin-3 (ATXN3) deubiquitinates the C-terminus of PARK2 (Parkin) (Winborn et al. 2008, Durcan et al. 2011). This promotes the degradation of PARK2. An unstable CAG trinucleotide repeat expansion in the ATXN3 gene leads to elongation of the polyglutamine (polyQ) tract within the ATXN3 protein, and is believed to be the cause of Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3), the most common dominantly inherited form of ataxia (Martins et al. 2007). Both wild-type and polyQ-expanded ATXN3 can deubiquitinate PARK2, regardless of the lysine residue used to assemble poly-Ub chains. The polyQ-expanded ATXN3 deubiquitinates PARK2 more efficiently than wild-type ATXN3, but the mutant rather than the wild-type ATXN3 promoted the clearance of PARK2 via the autophagy pathway. This apparent contradiction may be due to increased removal of K27- and K29-linked Ub conjugates on PARK2 by the polyQ-expanded ATXN3; Ub conjugates linked in this manner to PARK2 may protect it from autophagic degradation (Durcan et al. 2011).
Durcan, TM, Fon, EA, Williams, AJ, Djarmati, A, Fantaneanu, T, Kontogiannea, M, Fallon, L, Paulson, HL, Thorarinsdottir, T
Cohen, RE, Xu, P, Scaglione, KM, Peng, J, Williams, AJ, Winborn, BJ, Travis, SM, Paulson, HL, Todi, SV
cysteine-type deubiquitinase activity of ATXN3:polyUb-PARK2 [cytosol]
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