Heparin binding induces a conformational change in pigment epithelium-derived factor.
Pigment epithelium-derived factor (PEDF) is a noninhibitory serpin found in plasma and in the extracellular space. The protein is involved in different biological processes including cell differentiation and survival. In addition, it is a potent inhibitor of angiogenesis. The function is likely associated with binding to cell surface receptors in a heparin-dependent way (Alberdi, E. M., Weldon, J. E., and Becerra, S. P. (2003) BMC Biochem. 4, 1). We have investigated the structural basis for this observation and show that heparin induces a conformational change in the vicinity of Lys(178). This structural change was evident both when binding to intact heparin and specific heparin-derived oligosaccharides at physiological conditions or simply when exposing PEDF to low ionic strength. Binding to other glycosaminoglycans, heparin-derived oligosaccharides smaller than hexadecasaccharides (dp16), or type I collagen did not affect the structure of PEDF. The conformational change is likely to expose the epitope involved in binding to the receptor and thus regulates the interactions with cell surface receptors.
Valnickova
Zuzana
Z
Center for Insoluble Protein Structures (inSPIN), Department of Molecular Biology, University of Aarhus, DK-8000 Aarhus, Denmark.
Petersen
Steen V
SV
Nielsen
Søren B
SB
Otzen
Daniel E
DE
Enghild
Jan J
JJ
D001665:Binding Sites; D005136:Eye Proteins / Q000737:chemistry* / Q000378:metabolism*; D006493:Heparin / Q000378:metabolism*; D006801:Humans; D008239:Lysine; D009414:Nerve Growth Factors / Q000737:chemistry* / Q000378:metabolism*; D009844:Oligosaccharides; D009994:Osmolar Concentration; D011485:Protein Binding; D011487:Protein Conformation; D011956:Receptors, Cell Surface / Q000378:metabolism; D015843:Serpins / Q000737:chemistry* / Q000378:metabolism*; D000099174:Pigment Epithelium-Derived Factor
D005136:Eye Proteins; D006493:Heparin; D008239:Lysine; D009414:Nerve Growth Factors; D009844:Oligosaccharides; D011956:Receptors, Cell Surface; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor