Biology Reference
In-Depth Information
Model refinement
Many biological signaling processes in the human cell are well documented, for example the caspase
cascade of apoptosis [Jin and El-Deiry, 2005] or the communication network of cytokines between
immune cells [Haddad, 2002]. Reactions of these signaling pathways can be found in databases as K
EGG
[Kanehisa
et al.
, 2008] or T
RANSPATH
[Krull
et al.
, 2006]. Although the spliceosome is for many years
under investigation, no consistent and wholistic network has been published so far. Reactions involved
in spliceosome assembly were biochemically described, but not formalized (see Fig. 2). After setting
up the model of E-complex assembly, we iteratively included further reactions (assembly stages) and
revalidated the model. All PN representations in this study were created using the PN editor SNOOPY
[Rohr
et al.
, 2010].
RESULTS
Representation of functional modules as Petri nets
Inspired by previous suggestions [Reddy
et al.
, 1996; Takai-Igarashi, 2005; Chaouiya, 2007], we
designed at first a number of small net modules, which describe different reactions or interactions
between spliceosomal components. To reach a valid model, these net modules are useful for testing
modeling strategies, which appropriately reflect observed biologically behavior of parts of the network.
In general, the modeling of biological meaningful modules within signaling pathways strongly depends
on the depth of experimentally verified knowledge of the described mechanism.
The following net
modules have been used for modeling the basic reactions of spliceosomal assembly:
1.
Allosteric interaction
describes the process in which a protein binds to a specific domain of a target
protein, induces a conformational change at a distant site, and hence rendering the target protein
itself active or inactive. In spliceosomal processes this concept can be extended to the level of
protein complex association, where the binding of special factors is crucial for subsequent progress
through intermediate assembly stages. A module for this biochemical process is decomposable into
four T-invariants, two of which being cycles that describe the repeated association and disintegration
of the intermediate complex,
AB
, and the final complex,
ABC
(see Fig. 3). Note that dissociation is
restricted to
AB
+
C
or
A
+
B
+
C
, since
AC
or
BC
are “
forbidden
” by the allosteric rule imposed
during complex formation. The same model strongly reduces structural complexity by exhibiting
one T-invariant, covering all transitions.
Further special cases of allostery can be distinguished, and accordingly different net modules were
designed.
(a)
Allosteric inhibition
depends on the presence of a specific domain within a subcomplex.
An inhibitor may bind to the complex, inducing either disassembly or non-availability of the
complex for specific downstream interactions (see Fig. 4). This leads to an extension of the
module depicted in Fig. 3b. The heterodimer AB can either participate in further reactions
(
AB
+
C
), dissociate or bind to an inhibitory factor
I
. After sequestration of complex
AB
, the
non-functional complex
IAB
can not participate in the assembly pathway anymore. Thus, it
is modeled as output transition (
IAB out
). The module designed with dissociation reactions
again results in several T-invariants (data not shown), including sustained cycles of associations
and dissociations.
In contrast, the module reduced for dissociation reactions exhibits two
