title: Angiopoietins have distinct modular domains essential for receptor binding, dimerization and superclustering.
abstract: Angiopoietins are a recently discovered family of angiogenic factors that interact with the endothelial receptor tyrosine kinase Tie2, either as agonists (angiopoietin-1) or as context-dependent agonists/antagonists (angiopoietin-2). Here we show that angiopoietin-1 has a modular structure unlike any previously characterized growth factor. This modular structure consists of a receptor-binding domain, a dimerization motif and a superclustering motif that forms variable-sized multimers. Genetic engineering of precise multimers of the receptor-binding domain of angiopoietin-1, using surrogate multimerization motifs, reveals that tetramers are the minimal size required for activating endothelial Tie2 receptors. In contrast, engineered dimers can antagonize endothelial Tie2 receptors. Surprisingly, angiopoietin-2 has a modular structure and multimerization state similar to that of angiopoietin-1, and its antagonist activity seems to be a subtle property encoded in its receptor-binding domain.
authors.affiliation: Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA. samuel.davis@regeneron.com
authors.forename: Samuel
authors.initials: S
authors.lastname: Davis
authors.forename: Nick
authors.initials: N
authors.lastname: Papadopoulos
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Aldrich
authors.forename: Peter C
authors.initials: PC
authors.lastname: Maisonpierre
authors.forename: Tammy
authors.initials: T
authors.lastname: Huang
authors.forename: Lubomir
authors.initials: L
authors.lastname: Kovac
authors.forename: April
authors.initials: A
authors.lastname: Xu
authors.forename: Raymond
authors.initials: R
authors.lastname: Leidich
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Radziejewska
authors.forename: Ashique
authors.initials: A
authors.lastname: Rafique
authors.forename: Judah
authors.initials: J
authors.lastname: Goldberg
authors.forename: Vivek
authors.initials: V
authors.lastname: Jain
authors.forename: Kevin
authors.initials: K
authors.lastname: Bailey
authors.forename: Margaret
authors.initials: M
authors.lastname: Karow
authors.forename: Jim
authors.initials: J
authors.lastname: Fandl
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Samuelsson
authors.forename: Ella
authors.initials: E
authors.lastname: Ioffe
authors.forename: John S
authors.initials: JS
authors.lastname: Rudge
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Daly
authors.forename: Czeslaw
authors.initials: C
authors.lastname: Radziejewski
authors.forename: George D
authors.initials: GD
authors.lastname: Yancopoulos
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D042683:Angiopoietin-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D042702:Angiopoietin-2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D042682:Angiopoietins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D019281:Dimerization; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D008958:Models, Molecular; D010766:Phosphorylation; D011485:Protein Binding; D015202:Protein Engineering; D042787:Receptor, TIE-2 / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D042683:Angiopoietin-1; D042702:Angiopoietin-2; D042682:Angiopoietins; D011994:Recombinant Proteins; D042787:Receptor, TIE-2