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expressed in an
E. coli
expression system. All proteins retained func-
tional activity and were able to inhibit classical pathway-mediated
complement activation on an immunocomplex ELISA set.
The amino acids that are associated with the enhanced activity of
SPICE were identified by testing the ability of appropriate VCP/SPICE
chimeras to inhibit alternative pathway-mediated complement activa-
tion [16]. Furthermore, it was demonstrated that despite this enhanced
activity, SPICE cofactor activity in the factor I-mediated degradation of
C3b does not result in the cleavage of the
'-chain of C3b between
residues 956 and 957 to generate C3c and C3dg. The multi-log
10
increase
in the complement regulatory activity of SPICE when compared to
VCP permitted the systematic study of the domains and amino acid
changes that contributed to this enhanced activity and demonstrated
the role of electrostatics in the interaction of C3b with VCP and SPICE.
That is, a predominantly negative C3b and a predominantly positive
VCP variant favor their electrostatically driven recognition and enhance
their association. Increase in the positive charge of VCP variants occurs
by mutations of acidic amino acids, which reduce the negative character
of the electrostatic potential at the vicinity of SCR-2 and SCR-3 and
enhance the positive character of the electrostatic potential at SCR-1. This
model has important implications in both our understanding of how
RCA proteins interact with C3b and in the rational design of potent
complement inhibitors that might be used as therapeutic agents [66].
To define the mechanism by which other viral homologs of comple-
ment regulatory proteins interact with C3b and contribute to immune
evasion and pathogenesis, research efforts have focused on defining
the complement-neutralizing function of two viral proteins of the her-
pesvirus family: gC, a glycoprotein encoded by herpes simplex virus
type-1 (HSV-1) [67], and kaposica, a complement inhibitor encoded by
Kaposi's sarcoma-associated herpesvirus (KSHV) [68]. Studies using
animal gene knockout models and expressed recombinant proteins
have revealed several aspects of the molecular interaction between C3b
and gC/kaposica and will hopefully contribute to developing effective
therapeutics for the treatment of these viral diseases.
α
COMPLEMENT EVOLUTION AND DIVERSITY
Studies of evolutionary processes that give rise to living organisms as
they are known today constitute an integral part of modern biology.
A comprehensive understanding of any complex biological system
such as the complement system requires a thorough knowledge of its
origin and evolution, development, and diversity.
In this respect, it has recently been shown that teleost fish possess
multiple isoforms of various complement components, as a means of
expanding their innate immune capabilities and also compensating for
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