Milk fat globule epidermal growth factor 8 (MFG-E8) binds to oxidized phosphatidylserine: implications for macrophage clearance of apoptotic cells

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Milk fat globule epidermal growth factor 8 (MFG-E8) (also known as lactadherin) is a secreted glycoprotein, and consists of two EGF-like domains, a mucin-like domain, and tandem discoidin-like domains (C-domains); in addition, an RGD motif that binds to α_Vβ₃ and α_Vβ₅ integrins is present in the second EGF domain.¹ The C2 domain of MFG-E8 shares homology with the lipid-binding domains of blood coagulation factors VIII and V that have been shown to mediate Ca²⁺-independent, high affinity (K_d∼2 nM) binding to phosphatidylserine (PS).² Similarly, MFG-E8 is known to bind to PS via its C2 domain.³ Apoptotic cells express PS on the cell surface, and recent studies have suggested that MFG-E8 may act as a ‘bridging’ molecule that links apoptotic cells to phagocytes via its C1C2 domain and integrin-binding motif, respectively.⁴ However, MFG-E8 binding to phospholipids was not examined in detail. We have previously documented the occurrence of cell surface externalization of oxidized PS (PS-OX) during apoptosis, and have provided evidence that both species of PS (oxidized and nonoxidized) function as recognition signals for macrophages.^{5, 6} We now show that MFG-E8 preferentially interacts with PS-OX and, to a lesser degree, with nonoxidized PS and PC (phosphatidylcholine).

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