Supplementary text 3
The interaction partners of parkin
Parkin can interact with E2 ubiquitin conjugating enzymes, UbCH7 and UbCH8 at the
UBL domain (Shimura et al., 2000; Zhang et al., 2000). Parkin may work as a part of
the SCF-like (Skp1-Cullin-F-box protein) ubiquitin ligase complex where parkin
interacts with cullin1 and Fbox/WD (Staropoli et al., 2003). This proteasome complex
recognizes poly-ubiquitinated proteins for degradation. Parkin also interacts with Rpn10,
a subunit of the 26S proteosome complex, which is likely by to recognize proteins that
are poly-ubiquitinated by parkin (Sakata et al., 2003). Interaction of the 20S proteasome
subunit 4 with parkin at the IBR domain has also been reported, although the role of
the association is not clear (Dachsel et al., 2005). A wide variety of target substrates
have also been identified to be ubiquitinated by parkin through PPI search; septin 5, a
member of the septin gene family of nucleotide binding proteins involved in regulation
of cytoskeletal organization (Zhang et al., 2000), GPR37, the endothelin receptor type
B-like G protein coupled receptor (Imai et al., 2001), tubulin (Ren et al., 2003), p38
subunit of the aminoacyl-tRNA synthetase complex (Corti et al., 2003) and
synaptotagmin XI (Huynh et al., 2003). Recently, the mutated DJ-1, another protein
responsible for the hereditary PD, has been reported to associate with parkin, resulting
in inhibiting the parkin ubiquitination activity (Moore et al., 2005). Earlier association
works also revealed other characteristic of parkin; CASK, a PDZ domain-containing
protein, associates with the carboxyl-terminal of parkin, where CASK plays a role in
localization of parkin at synapses (Fallon et al., 2002). Association of parkin and
synphilin, a -synuclein binding protein, was identified and demonstrated to be
important for formation of Lewybody-like ubiquitin positive cytosolic inclusion (Chung
et al., 2001). Recent PPI information also provides regulation model for the parkin
protein. Bcl-2-associated athanogene 5 (BAG5), a BAG family member, directly
interacts with parkin and the chaperone Hsp70 (Kalia et al., 2004). BAG5 inhibits both
parkin E3 ubiquitin protein ligase activity and Hsp70-mediated refolding of misfolded
proteins. 14-3-3, one of the 14-3-3 family members, interacts directly with the
LINKER region of parkin and inhibits parkin E3 ubiquitin protein ligase activity (Sato
et al., 2006). Interestingly, 14-3-3 can interact tightly with -synuclein, another
hereditary PD protein, but not with the mutated -synuclein responsible for PD,
suggesting that failure in sequestration of 14-3-3 from parkin by mutated -synuclein
may attenuate parkin E3 ubiquitin protein ligase activity resulting in PD.
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