Collagen XVIII/endostatin structure and functional role in angiogenesis.
The angiogenesis inhibitor endostatin is a 20 kDA C-terminal fragment of collagen XVIII, a proteoglycan/collagen found in vessel walls and basement membranes. The endostatin fragment was originally identified in conditioned media from a murine endothelial tumor cell line. Endostatin inhibits endothelial cell migration in vitro and appears to be highly effective in murine in vivo studies. The molecular mechanisms behind the inhibition of angiogenesis have not yet been elucidated. Studies of the crystal structure of endostatin have shown a compact globular fold, with one face particularly rich in arginine residues acting as a heparin-binding epitope. It was initially suggested that zinc binding was essential for the antiangiogenic mechanism but later studies indicate that zinc has a structural rather than a functional role in endostatin. The generation of endostatin or endostatin-like collagen XVIII fragments is catalyzed by proteolytic enzymes, including cathepsin L and matrix metalloproteases, that cleave peptide bonds within the protease-sensitive hinge region of the C-terminal domain. The processing of collagen XVIII to endostatin may represent a local control mechanism for the regulation of angiogenesis.
Zatterstrom
U K
UK
Harvard Medical School, Department of Cell Biology, Boston, MA 02115, USA.
Felbor
U
U
Fukai
N
N
Olsen
B R
BR
D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002642:Chick Embryo; D003094:Collagen / Q000737:chemistry* / Q000378:metabolism*; D043170:Collagen Type XVIII; D043169:Endostatins; D004730:Endothelium, Vascular / Q000378:metabolism; D006801:Humans; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D043170:Collagen Type XVIII; D043169:Endostatins; D010446:Peptide Fragments; D003094:Collagen; D010447:Peptide Hydrolases