Insights into the ligand binding specificity of SREC‐II (scavenger receptor expressed by endothelial cells)

Abstract

SREC-II (scavenger receptor expressed by endothelial cells-II) is a membrane protein encoded by the SCARF2 gene, with high homology to class F scavenger receptor SR-F1, but no known scavenging function. We produced the extracellular domain of SREC-II in a recombinant form and investigated its capacity to interact with common scavenger receptor ligands, including acetylated low density lipoprotein (AcLDL) and maleylated or acetylated BSA (MalBSA or AcBSA). Whereas no binding was observed for AcLDL, SREC-II ectodomain interacted strongly with MalBSA and bound with high affinity to AcBSA, a property shared with the SR-F1 ectodomain. SREC-II ectodomain also interacted with two SR-F1 specific ligands, complement C1q and calreticulin, with affinities in the 100 nM range. We proceeded to generate a stable CHO cell line overexpressing full-length SREC-II; binding of MalBSA to these cells was significantly increased compared to non-transfected CHO cells. In contrast, no increase in binding could be detected for C1q and calreticulin. We show for the first time that SREC-II has the capacity to interact with the common scavenger receptor ligand MalBSA. In addition, our data highlight similarities and differences in the ligand binding properties of SREC-II in soluble form and at the cell surface, and show that endogenous protein ligands of the ectodomain of SREC-II, such as C1q and calreticulin, are shared with the corresponding domain of SR-F1.

Analysis of CRSsNP Proteome Using a Highly Multiplexed Approach in Nasal Mucus

“…[16][17][18][19] In contrast, SCARF2 was downregulated, although according to current knowledge it is associated with the same functions. 20,21 FOXP3, a transcription factor of regulatory T cells (Tregs), 22 was also found to be downregulated.…”

“…Shedding of SRs by exofacial proteases results in the release of soluble products to the circulation, whose functions can differ from those of the precursor protein. 20,21 Thus, a possible explanation for SCARF2 underexpression in CRSsNP mucus could be either an unknown function of its soluble ektodomain or an alteration in its shedding process driven by impaired protease activity.…”

“…The structural determinants of SCARF2 are a long cytosolic tail and several epidermal growth factor (EGF) and EGF-like domains which suggest that it is primarily involved in cell proliferation and differentation. 20,21 Generally, SRs are considered to be a subclass of the pattern recognition receptors (PRRs) playing an important role in innate immune response and thus in inflammation. Overall, scavenger activity was originally associated with the ability to bind and to internalize modified lipids and proteins including oxidized low-density lipoprotein.…”

“…20,49 However, there are different reports about whether SCARF2 exerts any scavenger activity 50 or not. 21 Hypothesizing why SCARF2 is downregulated in CRSsNP mucus is difficult. One possible explanation lies in the regulation process of PRRs.…”

Structure of scavenger receptor SCARF1 and its interaction with lipoproteins

“…It can also bind bacterial, viral, and fungal antigens [7, 22, 34, 35], but the mechanisms for having such diverse ligand binding properties are unclear. By contrast, SCARF2 shows no binding activity with modified LDLs [24, 36], but recent data suggest SCARF2 may share ligands such as complement C1q and calreticulin with SCARF1 [36]. In addition, MEGF10 (multiple EGF-like domains-10), which might be another member of SR-F family, is a mammalian ortholog of Ced-1 and a receptor of amyloid-β in the brain [13, 37, 38], suggesting that SR-F family members may have rather wide ligand binding specificities.…”