Structural characteristics of heparin-like domain required for interaction of midkine with embryonic neurons

Midkine is a heparin binding growth/differentiation factor with neurite promoting activity. We examined inhibitory activities of various heparin derivatives toward interaction of midkine with neurons and elucidated the structural requirements of the heparin-like domain necessary for the interaction. All of the three sulfate groups in the heparin disaccharide unit (6-O-sulfate, 2-O-sulfate and N-sulfate) were necessary for full inhibitory activity. Among these, the N-sulfate group was critically important. The minimum size with inhibitory activity was approximately 7,000 Da. Thus, the highly sulfated region in cell surface heparan sulfate proteoglycan is required for neurons to interact with midkine.