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PubMed · 10704302

Variable zinc coordination in endostatin.

E Hohenester·T Sasaki·K Mann·R Timpl
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Abstract

Endostatin is a proteolytic fragment of collagen XVIII that potently inhibits angiogenesis and tumour growth. Human endostatin contains a zinc ion, bound near the N terminus, which was not observed in the original structure of mouse endostatin at pH 5. Controversial data exist on the role of this zinc ion in the anti-tumour activity. We report two new crystal structures of mouse endostatin at pH 8.5 with bound zinc. One crystal form shows a metal ion coordination similar to that in human endostatin (His132, His134, His142, Asp207), but the conformation of the N-terminal segment is different. In the other crystal form, Asp136 replaces His132 as a zinc ligand. Site-directed mutagenesis of zinc-binding residues demonstrates that both coordination geometries occur in solution. The large degree of structural heterogeneity of the zinc-binding site has implications for endostatin function. We conclude that zinc is likely to play a structural rather than a critical functional role in endostatin.

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Amino Acid SequenceAmino Acid SubstitutionAnimalsAspartic AcidBinding SitesCollagenCollagen Type XVIIICrystallography, X-RayDimerizationEndostatinsHistidineHumansMiceModels, MolecularMolecular Sequence DataPeptide FragmentsProtein ConformationSolutionsStructure-Activity RelationshipZincJournal ArticleResearch Support, Non-U.S. Gov't

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E Hohenester, T Sasaki, K Mann, R Timpl. 2000-03-17. Variable zinc coordination in endostatin.. https://doi.org/10.1006/jmbi.2000.3553

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