Integrating Innate Immunity into a Global “Systems” Context: The Complement Paradigm Shift - Systems Biology: Networks, Models, and Applications - page 176

integrity of the regenerative process and their potential use as thera-
peutic targets.
In the postgenomic era, it is anticipated that the integrated use of
proteomic technologies will serve as a powerful analytical tool in the
study of C3-ligand interactions by helping researchers to better define
and monitor the dynamic protein changes that underlie various com-
plement-dependent biological responses.
Thermodynamic Studies of Complement Protein-Protein Interactions
Isothermal titration calorimetry (ITC) is a method used to study ener-
getics of the formation of macromolecular complexes in solution that
have association constants in the range ~10 3 -10 9 M −1 . It measures the
electric power that is required to reequilibrate the temperature of a
binding reaction cell with respect to a reference cell as a function of
time, upon binding [60], and yields information on the stoichiometry,
enthalpy, association constant, and free energy of binding. ITC has
recently been applied to the study of energetics of the interaction of
C3 with its inhibitor, compstatin. Thermodynamic measurements
have indicated that the binding of compstatin to C3 is 1:1 and occurs
through hydrophobic interactions with possible conformational
changes in C3 or compstatin. Some protonation changes, occurring at
the binding interface, have also been observed by ITC analysis [61].
This analysis will be extended to the energetics of various protein-
protein interactions, with the goal of obtaining the energetic parameters
of complement activation and regulation pathways.
The Complement System and Viral Molecular Mimicry
The complement system serves as both an innate and an acquired
defense against viral infection. Activation of the complement (C')
system in the presence or absence of antibodies can lead to virus neu-
tralization, phagocytosis of C3b-coated viral particles, lysis of infected
cells, and generation of inflammatory and specific immune responses.
To circumvent these defenses, viruses have not only developed mech-
anisms to control C' but have also turned these interactions to their
own advantage. Given the clinical importance of devising effective
antiviral therapeutics, considerable attention has been devoted in
recent years to the structural and functional analysis of several viral
proteins (such as, VCP/SPICE, gC, and kaposica) that are involved in
C' evasion.
VACCINIA VIRUS IMMUNE EVASION STRATEGIES : STUDIES ON THE
C 3b/ VCP INTERACTION
Vaccinia virus complement control protein (VCP) is a 35 kDa secretory
protein of vaccinia virus that contains four short consensus repeats
(SCRs) [62]. The protein shows homology to C4-binding protein (C4Bp)