Computational Molecular Biology 2016, Vol.6, No.1, 1-20
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which interact and form a further complicated network. A better understanding of the pathway may provide the
missing links and new targets for designing and developing drugs. In this review, we focused on the molecular and
computational modeling studies which decipher the cross-talks of the NFkB pathway. This review also focuses on
the understanding of function of E3 ligases and their inhibitors and how computational tools can help in finding
new potential drug candidates using virtual screening and QSAR studies.
2 Pathways for NFkB activation
The canonical and the non-canonical pathways are the two major pathways involved in the NFkB signaling. In the
canonical pathway, signals are received from the receptors like tumour necrosis factor receptor (TNFR),
interleukin 1 receptor IL-1R and toll like receptors (TLRs). This pathway is mainly dependent on phosphorylation
of IkB by IKK-B and NEMO, which leads to IkB degradation by the ubiquitin-proteosomal pathway (UPS).
Following degradation of IkB, the NFkB particles mostly p65 are released. The homo/hetero dimmers then
translocate to the nucleus with the help of importing proteins and bind the DNA to carry out the process of
transcription. Phosphorylation of two serine residues (Ser 177,181) in the activation loop of IKKB kinase
enhances its activity (Gilmore, 2006; Perkins and Gilmore, 2006).
The non-canonical pathway regulates specific immunological processes by using several specific IkB family
members.
In contrast to the IkB degradation in the canonical pathway, the non-canonical pathway depends on the
phosphorylation and auto-proteolysis of the NFkB factor p105 and p100. The C-terminal domain of p105 and
p100 exhibits structural homology with the IkB and inhibit the nuclear localization of associated NFkB factors by
masking their NLS domain. The processing of p100 is suppressed by C-terminal portion. The C-terminal portion
of contains a processing inhibitory domain (PID) and an ankyrin repeat domain (ARD). The PID consists of a
death domain (DD) structure whereas the ARD is known to mask the nuclear localization s ignal (NLS) present in
the N-terminal Rel-homology domain of p100. p100 is phosphorylated at two C-terminal serine residues by IKK-a
homodimer along with NFkB inducing factor (NIK) upon reception of signal(Sun, 2010, 2012). NIK is subjected
to continuous degradation by TRAF3 E3 ubiquitin ligase under normal cellular environment. Recent research
showed that NIK ubiquitin ligase is composed of TRAF3, TRAF2 and cIAP1, in which TRAF3 f unctions as a
substrate binding subunit for NIK. Upon reception of signal from a specific sub-set of TNF receptor superfamily,
TRAF3 degradation is initiated leading to NIK stabilization and hence its accumulation (Sanjo et al., 2010; Sun,
2012). NIK accumulation and its association with IKK-α leads to ubiquitination of p100 which produces p52. p52
is known to prefentially bind RelB, hence UPS degradation of p100 leads to the nuclear localization of p52/RelB
complex.
There are additional NFkB pathways which do not depend on IKK action (Li et al., 2010). Pathways like
UV induced NFkB activation does not appear to use the IKK complex. Phosphorylation of IkB-α at Tyr 42 alone
leads to the activation of NFkB pathway (Campbell
et al.,
2001). NFkB is a complex pathway controlling many
cellular processes which involves many factors upstream as well as downstream. The different transcriptional
factors have specified binding regions in the DNA. Separate NFkB factors are involved in the activation of
different target genes.
2.1 Cross-talk of NFkB with other pathways
NFkB pathway regulates a broad spectrum of biological processes in the cell. The question raises that, how a few
set of proteins of the NFkB pathway can regulate such diverse number of cellular processes. Research
demonstrates that NFkB pathway is not quarantine and our picture of NFkB pathway is mostly one-dimensional.
Biological signaling is mostly defined by the feedback circuits which include dynamic circuit networks. The
function of its constituents are mostly described not only by its individual function but also by their interactions
and cross-talks with the components of other signaling pathways (Oeckinghaus et al., 2011). NFkB pathway has
numerous parallel interaction networks and cooperativities with various other pathways. NFkB interacts with
PI3/AKT pathway (Hussain et al., 2012) in modulating anti-apoptosis in lymphoma cells, also reactive oxygen
species (ROS) which interacts at various points within the signaling pathway to activate or deactivate the NFkB
pathway are examples of cross-talk of NFkB with other components in the cell(Morgan and Liu, 2010). Seeking
