Role of the ubiquitin-like modifier FAT10 in protein degradation and ...

Introduction
majority of ubiquitin-protein ligases fall into one of two subcategories, the HECT-
domain E3s or the RING-finger E3s (Fang and Weissman, 2004).
The HECT (Homologous to E6-AP C-terminus)-domain family was the first family
of ubiquitin-ligases to be identified. The first member of this family, E6-AP, was
discovered as a cellular protein which was required for the ubiquitylation and sub-
sequent degradation of the p53 tumor suppressor by the human pappilomavirus
E6 oncoprotein (Scheffner et al., 1994). HECT-domain E3s first transfer ubiquitin
from the bound E2 onto their active site cysteine in the C-terminal HECT-domain
before they pass it on to their substrate protein.
The RING (Really Interesting New Gene)-domain family is the largest family of
ubiquitin-ligases. The RING-finger is defined by eight conserved cysteines and
histidines which together coordinate two zinc ions (Borden and Freemont, 1996).
The first member of this family which was identified is the ubiquitin-ligase E3α,
which is responsible for ubiquitylating substrates of the N-end rule pathway.
RING-domain E3s do not transfer the activated ubiquitin onto themselves, but
rather facilitate its transfer from the tightly bound E2 directly onto the substrate
protein. This family of E3s consists of both single subunit enzymes, which contain
all the necessary domains in one protein, for example Cbl, as well as large multi-
meric complexes such as the SCF-complex, or the anaphase-promoting-complex,
in which the RING domain exists as a separate subunit (Joazeiro and Weissman,
2000).
The other two subfamilies are relatively small and both contain variants of
the RING-domain. The PHD-finger was first identified as a component of viral
ubiquitin-ligases, but has subsequently also been found in mammalian proteins
(Coscoy and Ganem, 2003). The U-box, in turn, is a modified RING-domain with
no coordinated zinc ions. The ubiquitin-ligase CHIP for example, which functions
as an E3 for HSP90 interacting proteins, is a member of this last family (Jiang
et al., 2001).
In contrast to the large number or E3 enzymes, the mammalian genome encodes
for only about 30 different E2 ubiquitin-conjugating enzymes (von Arnim, 2001).
As a consequence, each E2 enzyme is responsible for serving a number of differ-
ent E3s. All known E2 enzymes belong to the same family, which is characterized
by the presence of a catalytic domain called the UBC-domain. Some E2s possess
additional C-terminal or N-terminal extensions, which are responsible for medi-
ating subcellular localization or recognition of E3 enzymes. With a few exceptions
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