title: Crystal structure of the LG3 domain of endorepellin, an angiogenesis inhibitor.
abstract: Endorepellin, the C-terminal region of perlecan, inhibits angiogenesis by disrupting actin cytoskeleton and focal adhesions. The C-terminal laminin-like globular domain (LG3) of endorepellin directs most of this antiangiogenic activity. To investigate the angiostatic mechanism and to identify structural determinants, we have solved crystal structures of the LG3 domain in both apo- and calcium-bound forms at resolutions of 1.5 Å and 2.8 Å, respectively. The conserved core has the jellyroll fold characteristic of LG domains. The calcium-induced structural changes seem very restricted, and the calcium binding site appears to be preformed, suggesting that the bound calcium ion, rather than structural rearrangements, contributes to antiangiogenesis. We have identified H4268 on the EF loop as a key residue for the biochemical function of LG3, since its mutation abolishes antiangiogenic activity, and mutant LG3 can no longer form a direct interaction with integrin. Taken together, we propose that these two distinct structural elements contribute to the angiostatic effect of endorepellin.
authors: Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746, Korea.
authors: Binh V
authors: BV
authors: Le
authors: Hun
authors: H
authors: Kim
authors: Jongkeun
authors: J
authors: Choi
authors: Jin-Hahn
authors: JH
authors: Kim
authors: Myong-Joon
authors: MJ
authors: Hahn
authors: Cheolju
authors: C
authors: Lee
authors: Kyeong Kyu
authors: KK
authors: Kim
authors: Hye-Yeon
authors: HY
authors: Hwang
mesh_terms: D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D018360:Crystallography, X-Ray; D019812:Heparan Sulfate Proteoglycans / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D017386:Sequence Homology, Amino Acid
chemical_list: D020533:Angiogenesis Inhibitors; D019812:Heparan Sulfate Proteoglycans; D010446:Peptide Fragments; C071927:perlecan; D002118:Calcium