Computational Molecular Biology 2016, Vol.6, No.1, 1-20
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4.1.2 RING
In mammals more than 600 genes code for RING E3 ligases (Deshaies and Joazeiro). ARING domain coordinates
a pair of zinc ions and contains 50-60 amino acids. RING domain was discovered by Freemont et al., in
1991(Freemont et al., 1991). The conserved Cys and His residues of RING domain are buried in the core probably
for maintaining the overall structure. The two zinc ions and the interacting residues form a criss-brace motif
(Deshaies and Joazeiro). However the RING domain of TRAF6 does not form any criss-brace motif, the Cys
residue in the C-terminal involved in Zn ion binding is replaced by an Asp residue (Mercier et al., 2007). The
RING unlike the HECT do-not form a catalytic site rather it forms a scaffold or linker to bring the E2 and the
substrate in close proximity. The zinc binding sites in the RING finger form a rigid structure essential for
protein-protein interactions; this unique feature distinguishes them from the Zn fingers (Metzger et al., 2010).
RING E3s can function as monomers, dimmers or oligomers. RING domain is involved in the process of
dimerization (Liew et al., 2010; Yudina et al., 2015) to form a higher order structure for interacting with E2. Some
of the important examples of RING E3 ligases as good prospects for drug targeting are: TRAF family proteins,
Parkin, SCF-cullin and MDM2. These E3 ligases are involved in the progression of chronic inflammation which
leads to cancer progression and neurodegenerative diseases.
4.1.2.1 TRAF
TRAF derives its name from tumor necrosis factor receptor associated factor and as the name implies binds the
TNF receptor to its cytoplasmic side. Six known members for the TRAF family TRAF (1-6) are known till date.
All TRAFs except for TRAF1 contain RING domain on its N-terminal end. Besides working as E3 ligases,
TRAFs work also work as adaptor proteins associating upstream and downstream signaling factors. TRAF2, 3, 5
and 6 function as E3 ligases. TRAF6 is a major E3 ligase apart from interacting with TNF receptors also interacts
with interlukin-1 (IL-1) receptor and toll-like receptor (TLR) superfamily to mediate immunological responses.
This very property makes TRAF6 unique and different from other TRAF members. TRAFs consist of an
N-terminal RING domain which is followed by zinc fingers and a conserved C-terminal MATH/TRAF domain
(Figure 2). MATH/TRAF domain is engaged in receptor recognition and oligomerisation (Lamothe et al., 2008;
Wu and Arron, 2003). Sequence analysis studies reveal diversity in the C-terminal domain and gene structure of
TRAF6. TRAF6 engages in E3 ubiquitin ligase activities by interac ting with E2 hUbc13 through the RING
domain. Studies on TRAF6-E2 association suggest that RING domain alone is not sufficient for the interaction
and requires the involvement of the first zinc finger (ZF1) (Yin et al., 2009). There is always fixed spacing in
between the zinc fingers of all members of TRAFs representing a conserved feature of the zinc finger arrangement
(Yin et al., 2009). Reports suggest TRAF6 ubiquitinates and activates the Akt signaling pathway(Yang et al.,
2009).
Figure 2 TRAF6 E3 ubiquitin ligase
