The seven-span transmembrane receptor CD97 has a cellular ligand (CD55, DAF).

A novel member of the EGF-TM7 family, mEMR4, was identified and characterized. The full-length mouse EMR4 cDNA encodes a predicted 689-amino acid protein containing two epidermal growth factor (EGF)-like modules, a mucin-like spacer domain, and a seventransmembrane domain with a cytoplasmic tail. Genetic mapping established that mEMR4 is localized in the distal region of mouse chromosome 17 in close proximity to another EGF-TM7 gene, F4/80 (Emr1). Similar to F4/80, mEMR4 is predominantly expressed on resident macrophages. However, a much lower expression level was also detected in thioglycollateelicited peritoneal neutrophils and bone marrowderived dendritic cells. The expression of mEMR4 is up-regulated following macrophage activation in Biogel and thioglycollate-elicited peritoneal macrophages. Similarly, mEMR4 is over-expressed in TNF-␣-treated resident peritoneal macrophages, whereas interleukin-4 and -10 dramatically reduce the expression. mEMR4 was found to undergo proteolytic processing within the extracellular stalk region resulting in two protein subunits associated noncovalently as a heterodimer. The proteolytic cleavage site was identified by N-terminal amino acid sequencing and located at the conserved GPCR (G protein-coupled receptor) proteolytic site in the extracellular region. Using multivalent biotinylated mEMR4-mFc fusion proteins as a probe, a putative cell surface ligand was identified on a B lymphoma cell line, A20, in a cell-binding assay. The mEMR4-ligand interaction is Ca 2؉ -independent and is mediated predominantly by the second EGF-like module. mEMR4 is the first EGF-TM7 receptor known to mediate the cellular interaction between myeloid cells and B cells.

mentioning

confidence: 99%

mentioning

confidence: 99%

EMR4, a Novel Epidermal Growth Factor (EGF)-TM7 Molecule Up-regulated in Activated Mouse Macrophages, Binds to a Putative Cellular Ligand on B Lymphoma Cell Line A20

Stacey¹,

Chang²,

Sanos³

et al. 2002

“…The most N-terminal SCR (domain 1) also provides the site of interaction for some viruses but until recently the native role of domain 1 was unknown. However, identification of CD97 as a cellular ligand for the N-terminal domains of CD55 (12,13) has now demonstrated a novel natural function associated with this portion of the molecule. CD97 is a member of the EGF-TM7 family, characterized by the unique chimeric structure in which tandem EGF repeats are coupled to a G protein-coupled receptor moiety via a mucin-like stalk region (14,15).…”

mentioning

confidence: 99%

Molecular Analysis of the Epidermal Growth Factor-like Short Consensus Repeat Domain-mediated Protein-Protein Interactions

Lin

Stacey

Saxby

et al. 2001

109

118

Epidermal growth factor-like (EGF) and short consensus repeat (SCR) domains are commonly found in cell surface and soluble proteins that mediate specific protein-protein recognition events. Unlike the immunoglobulin (Ig) superfamily, very little is known about the general properties of intermolecular interactions encoded by these common modules, and in particular, how specificity of binding is achieved. We have dissected the binding of CD97 (a member of the EGF-TM7 family) to the complement regulator CD55, two cell surface modular proteins that contain EGF and SCR domains, respectively. We demonstrate that the interaction is mediated solely by these domains and is characterized by a low affinity (86 M) and rapid off-rate (at least 0.6 s ؊1 ). The interaction is Ca 2؉ -dependent but is unaffected by glycosylation of the EGF domains. Using biotinylated multimerized peptides in cell binding assays and surface plasmon resonance, we show that a CD97-related EGF-TM7 molecule (termed EMR2), differing by only three amino acids within the EGF domains, binds CD55 with a K D at least an order of magnitude weaker than that of CD97. These results suggest that low affinity cell-cell interactions may be a general feature of highly expressed cell surface proteins and that specificity of SCR-EGF binding can be finely tuned by a small number of amino acid changes on the EGF module surface.

“…Recent studies have shown that it is involved in coordinating the innate immune response to bacterial pathogens by enhancing natural killer cell activity (5). Additionally, CD55 binds CD97, a member of the epidermal growth factor (EGF)-TM7 protein family, the expression of which is rapidly up-regulated upon activation of T and B cells (6).…”

mentioning

confidence: 99%

“…Complement control requires SCR2-4 (10), whereas CD97 binding only involves SCR1 (6). Among the CD55-binding enteroviruses, there are clear differences in the SCR domains bound (a few exclusively need SCR1 (11,12)), whereas all the echoviruses require at least paired SCR domains, consisting of SCR3 linked to either SCR2 and/or SCR4 (13).…”

mentioning

confidence: 99%

Mapping CD55 Function

Williams

Chaudhry

Goodfellow

et al. 2003

Decay-accelerating factor (CD55), a regulator of the alternative and classical pathways of complement activation, is expressed on all serum-exposed cells. It is used by pathogens, including many enteroviruses and uropathogenic Escherichia coli, as a receptor prior to infection. We describe the x-ray structure of a pathogen-binding fragment of human CD55 at 1.7 Å resolution containing two of the three domains required for regulation of human complement. We have used mutagenesis to map biological functions onto the molecule; decayaccelerating activity maps to a single face of the molecule, whereas bacterial and viral pathogens recognize a variety of different sites on CD55.