Angiopoietins have distinct modular domains essential for receptor binding, dimerization and superclustering.
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.
Davis
Samuel
S
Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA. samuel.davis@regeneron.com
Papadopoulos
Nick
N
Aldrich
Thomas H
TH
Maisonpierre
Peter C
PC
Huang
Tammy
T
Kovac
Lubomir
L
Xu
April
A
Leidich
Raymond
R
Radziejewska
Elzbieta
E
Rafique
Ashique
A
Goldberg
Judah
J
Jain
Vivek
V
Bailey
Kevin
K
Karow
Margaret
M
Fandl
Jim
J
Samuelsson
Steven J
SJ
Ioffe
Ella
E
Rudge
John S
JS
Daly
Thomas J
TJ
Radziejewski
Czeslaw
C
Yancopoulos
George D
GD
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
D042683:Angiopoietin-1; D042702:Angiopoietin-2; D042682:Angiopoietins; D011994:Recombinant Proteins; D042787:Receptor, TIE-2