STRUCTURE AND FUNCTION OF COMPLEMENT RECEPTORS 
V Michael Holers, M.D., Assistant Investigator 
One of the many functions of the complement 
system is to place activated forms of complement 
components C3 and C4 onto the surface of targets. 
These targets include immune complexes, as well 
as foreign soluble and particulate antigens. After co- 
valent attachment of activated C3 on the target, 
specific proteolytic processing steps occur on the 
C3 molecule that result in at least three major 
ligand forms. These forms each have a high affinity 
for a distinct C3 receptor. Depending on the cell 
type in which these receptors are expressed, C3- 
containing ligands are either transported to other 
tissue sites or are bound, internalized by phagocytic 
and/or endocytic mechanisms, and then processed. 
The intracellular fate of specific ligand-receptor 
complexes is incompletely understood. 
Dr. Holers and his colleagues have been analyz- 
ing one of the complement receptors, complement 
receptor 2 (CR2), and have utilized it as a model for 
the function, regulation of expression, and mecha- 
nisms of action of these receptors. CR2 is an —145 
kDa single-chain receptor expressed primarily on 
human B cells, follicular dendritic cells, and some 
epithelial cells. It is a member of a family of comple- 
ment regulatory and binding proteins, known as 
the regulators of complement activation, which is 
found in a single genetic locus on human chromo- 
some lq32. CR2 interacts with a peptide sequence 
on a form of activated and proteolytically processed 
C3 known as C3d. In addition, recent work has es- 
tablished that CR2 also functions as the receptor 
for the Epstein-Barr virus (EBV). EBV is a human 
pathogen that causes most clinical cases of infec- 
tious mononucleosis and is also causally associated 
with lymphoid and nonlymphoid tumors. 
CR2 is present primarily on mature, surface IgM- 
positive B cells and is not found at detectable levels 
on early pre-B cells, lymphoid progenitors, or late 
fully differentiated immunoglobulin-secreting B 
cells. Binding of ligand or some monoclonal anti- 
bodies to CR2 results in a coproliferative stimulus 
to resting peripheral or tonsillar B cells. CR2 is part 
of a growing family of B cell membrane proteins 
that are developmentally regulated and are proba- 
bly involved in the control of steps in B cell ontog- 
eny and activation. 
Another receptor expressed on B cells in a devel- 
opmentally regulated fashion is the human fibro- 
nectin receptor VLA-5. VlA-5 is a member of the in- 
tegrin gene family. Members of this family function 
in adherence of cells to matrix proteins and to 
other cells. In a number of model systems, these re- 
ceptors play important roles in targeting of cells to 
specific sites during development and to other sites 
later in life. 
Dr. Holers and his colleagues have been studying 
the expression of VLA-5 on phagocytic cells, be- 
cause it appears to help regulate the function of 
complement receptors on these cells. The labora- 
tory has also recently begun to analyze the function 
and regulation of expression of this receptor on 
human B cells. 
I. Complement Receptor 2. 
Previous studies by Dr. Holers and others had in- 
dicated that the primary structure of CR2 consists 
of either 15 or 16 short consensus repeats (SCRs), 
followed by transmembrane and intracytoplasmic 
domains. SCRs are —60-70 amino acids in length, 
have four invariant cysteines and a tryptophan at 
the same position in each repeat, and have other 
highly conserved but not invariant amino acids at 
other positions. This type of repeat is found in 
complement regulatory proteins and also increas- 
ingly in other proteins and receptors, such as those 
involved in lymphocyte homing. 
One goal of the laboratory is to identify and char- 
acterize the functional domains on CR2. These in- 
clude those in the extracellular domain involving 
the ligand-binding sites for both C3d and EBV Re- 
cent studies using deletion mutagenesis have indi- 
cated that single binding sites are found for both of 
these ligands in the most amino-terminal SCRs of 
CR2. Previous work on the genomic organization 
of CR2 had shown that the extracellular domain 
evolved through successive duplications in the ge- 
nome of a four-SCR-containing motif Despite there 
being four duplications of a four-SCR-containing re- 
peat, only one SCR appears to contain a binding 
site, and it is in the most amino-terminal duplica- 
tion. The function of the more proximal SCRs re- 
mains unclear. They may act to extend the distal re- 
peat away from the cell membrane, to interact with 
other membrane receptors or other CR2 molecules 
to form multireceptor complexes, or to mediate or 
facilitate transmembrane signaling events. Studies 
are ongoing to address these questions. CR2 also 
has a short intracellular domain. Deletion of this 
domain leads to defects in the ability of CR2 to me- 
Continued 
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