My
major research interest is the study of protein structure/function
relationships, using the third component of complement
(C3) as a model. Complement C3 is a multifunctional protein
that plays a central role in the activation and regulation
of the alternative pathway of complement. C3 binds another
complement protein, factor B, to form a serine protease
(C3 convertase, C3b,Bb) that serves to activate other C3
and C5 molecules. The C3 convertase is subject to regulation
by a number of other complement proteins, such as factors
H and I, and Complement receptors CR1, CF2, CR3, etc. These
proteins serve to regulate complement by either causing
dissociation of the C3 convertase or cleaving the active
form of C3 to inactivate it.
Cobra
venom contains a structural and functional analog of
C3, Cobra Venom Factor (CVF). Like C3, CVF is able to form
a C3 convertase by binding factor B. However, this convertase
is several orders of magnitude more stable than the C3
containing enzyme, and is not subject to regulation by
other complement proteins. Our laboratory has cloned
and
sequenced both CVF and cobra C3. The two proteins are
very similar one another (>90%
homology at both the DNA and protein levels) and to C3
proteins from other species (>50% DNA homology, ~70%
protein homology). We are using the relationships between
CVF and C3 proteins to define the structural elements
required for the unique CVF functions. For example, we
have demonstrated
that the C-terminal region of the larger chain of C3
(the a-chain) is involved
in the binding or cleavage of substrate
C3 or C5 molecules, and that the central portion of this
chain may be responsible for the stable binding of the
enzymatically active portion of the C3 convertase, Bb.
In a related project, we are developing a C3 analog that
is similar to CVF in stability and resistance to regulation,
but is not highly immunogenic. To this end, we have prepared
several hybrid human C3 proteins in which portions of
the C-terminus of the a-chain
have been replaced with homologous
CVF sequences and demonstrated that these hybrids have
varying amounts of CVF-like activity. These, or similar
proteins could be used to deplete complement in patients
requiring xenotransplants, or could be conjugated to
antibodies for use as an anti-tumor therapeutic.
In
addition, I have an interest in DNA sequencing technology
and in
genomics, as well as in methods for studying gene regulation
and gene expression.
Selected
Publications
Kock,
M.A., Hew, B.E., Bammert, H., Fritzinger, D.C. and Vogel, C.-W. (2004) “Structure and function of recombinant cobra venom
factor.” J. Biol Chem. 279, 30836-30843.
Vogel,
C.-W., Fritzinger, D.C., Hew, B.E., Thorne, M., and Bammert,
H. (2004) “Recombinant cobra venom factor.” Mol.
Immunol. 41, 191-199.
Hew,
B.E., Thorne, M., Fritzinger, D.C., and Vogel, C.-W. (2004) “Humanized
Cobra Venom Factor (CVF): generation of human C3 derivatives
with CVF-like function.” Mol. Immunol. 41, 244 (abstract).
Fritzinger,
D.C., Hew, B.E., Thorne, M., and Vogel, C.-W. (2004) “Functional
characterization of cobra venom factor/cobra C3 hybrid proteins.” Mol.
Immunol. 41, 230 (abstract).
Bammert,
H., Fritzinger, D.C., Bredehorst, R., Nonaka, M., and Vogel,
C.-W. (2004) “A phylogenetic study of the presence of
intron 31 in the complement C3 genes of vertebrates.” Mol.
Immunol. 41, 206 (abstract).
Artenstein,
A.W., Fritzinger, D.C., Gasser, R.A., Jr., Skillman, L.P.,
McEvoy, P. L., and Hadfield, T.L., (1994) "Infection Due
to Mycobacterium haemophilum Identified by Whole Cell Lipid
Analysis and Nucleic Acid Sequencing." Clinical Infectious
Diseases 19, 1155-1157.
