The angiogenic inhibitor long pentraxin PTX3 forms an asymmetric octamer with two binding sites for FGF2.
The inflammation-associated long pentraxin PTX3 plays key roles in innate immunity, female fertility, and vascular biology (e.g. it inhibits FGF2 (fibroblast growth factor 2)-mediated angiogenesis). PTX3 is composed of multiple protomers, each composed of distinct N- and C-terminal domains; however, it is not known how these are organized or contribute to its functional properties. Here, biophysical analyses reveal that PTX3 is composed of eight identical protomers, associated through disulfide bonds, forming an elongated and asymmetric, molecule with two differently sized domains interconnected by a stalk. The N-terminal region of the protomer provides the main structural determinant underlying this quaternary organization, supporting formation of a disulfide-linked tetramer and a dimer of dimers (a non-covalent tetramer), giving rise to the asymmetry of the molecule. Furthermore, the PTX3 octamer is shown to contain two FGF2 binding sites, where it is the tetramers that act as the functional units in ligand recognition. Thus, these studies provide a unifying model of the PTX3 oligomer, explaining both its quaternary organization and how this is required for its antiangiogenic function.
Inforzato
Antonio
A
Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom.
Baldock
Clair
C
Jowitt
Thomas A
TA
Holmes
David F
DF
Lindstedt
Ragnar
R
Marcellini
Marcella
M
Rivieccio
Vincenzo
V
Briggs
David C
DC
Kadler
Karl E
KE
Verdoliva
Antonio
A
Bottazzi
Barbara
B
Mantovani
Alberto
A
Salvatori
Giovanni
G
Day
Anthony J
AJ
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002097:C-Reactive Protein / Q000737:chemistry / Q000502:physiology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004220:Disulfides / Q000737:chemistry; D016222:Fibroblast Growth Factor 2 / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D009389:Neovascularization, Pathologic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry; D000683:Serum Amyloid P-Component / Q000737:chemistry / Q000502:physiology*; D000099153:Pentraxins
D020533:Angiogenesis Inhibitors; D002097:C-Reactive Protein; D004220:Disulfides; D016222:Fibroblast Growth Factor 2; D008024:Ligands; D011994:Recombinant Proteins; D000683:Serum Amyloid P-Component; D000099153:Pentraxins