Crystal Structure of the Bovine Lactadherin C2 Domain, a Membrane Binding Motif, Shows Similarity to the C2 Domains of Factor V and Factor VIII

Abstract

Lactadherin, a glycoprotein secreted by a variety of cell types, contains two EGF domains and two C domains with sequence homology to the C domains of blood coagulation proteins factor V and factor VIII. Like these proteins, lactadherin binds to phosphatidylserine (PS)-containing membranes with high affinity. We determined the crystal structure of the bovine lactadherin C2 domain (residues 1 to 158) at 2.4 Å. The lactadherin C2 structure is similar to the C2 domains of factors V and VIII (rmsd of C α atoms of 0.9 Å and 1.2 Å, and sequence identities of 43% and 38%, respectively). The lactadherin C2 domain has a discoidin-like fold containing two β-sheets of five and three antiparallel β-strands packed against one another. The N and C termini are linked by a disulfide bridge between Cys1 and Cys158. One β-turn and two loops containing solvent-exposed hydrophobic residues extend from the C2 domain β-sandwich core. In analogy with the C2 domains of factors V and VIII, some or all of these solvent-exposed hydrophobic residues, Trp26, Leu28, Phe31, and Phe81, likely participate in membrane binding. The C2 domain of lactadherin may serve as a marker of cell surface phosphatidylserine exposure and may have potential as a unique anti-thrombotic agent.