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Nedd8
is a ubiquitin-like small protein modifier. The
Nedd8 conjugation process, called neddylation, is
similar to ubiquitination. Neddylation utilizes
the E1 activating-enzyme complex composed of two
subunits, APP-BP1 and UBA3, and the E2 conjugating-enzyme,
UBC12 (Yeh, 2000). The only known substrates of
neddylation are Cullin family proteins -- Cul1,
Cul2, Cul3, Cul4A, Cul4B, and Cul5 -- which have
been shown to be modified by Nedd8 in mammalian
cells. Cullins directly interact with Roc1, a Ring
finger protein, and the Cullin-Roc1 complex comprises
the core module of a series of ubiquitin E3 ligases,
which confer substrate specificity and therefore
regulate the degradation process. Among Cullins,
many studies focused on Cul1, an essential component
of the SCF complex which functions as ubiquitin
E3 ligase. The SCF complex consists of core subunits:
Skp1, Cul1/Cdc53, Roc1/Hrt/Rbx1, and a substrate-recognition
F-box protein. Cul1 functions as a scaffold protein
within the SCF complex; the N-terminal domain of
Cul1 interacts with the adaptor protein Skp1 that
links with the F-box protein, and the C-terminal
domain interacts with Roc1 and the ubiquitin E2
enzyme (Ou, 2002 and references therein).
In vitro, neddylation of Cul1 is required for ubiquitination
of IkappaBalpha and p27Kip1 (Morimoto, 2000; Podust,
2000; Read, 2000). In addition, neddylation enhances
E2-ubiquitin recruitment to SCF. In fission yeast,
Nedd8 is essential for the SCF-mediated degradation
of Rum-1, a cyclin-dependent kinase inhibitor. In
Arabidopsis thaliana, the Nedd8 pathway is required
for SCF-mediated Auxin response. In mice deficient
for UBA3, a subunit of the E1 enzyme in neddylation,
embryonic development is aberrant, with accumulation
of two putative SCF substrates, ß-catenin
and cyclin E (Ou, 2002 and references therein).
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