Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 285, Issue 23, Pages 17681-17692Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M109.085639
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Funding
- Sigma-Tau
- Tecnogen
- Arthritis Research UK [16539]
- Medical Research Council [G0701180]
- European Research Council
- Fondazione Italiana per la Ricerca sul Cancro
- Fondazione Humanitas per la Ricerca
- Associazione Italiana per la Ricerca sul Cancro Funding Source: Custom
- Medical Research Council [G0701180] Funding Source: researchfish
- MRC [G0701180] Funding Source: UKRI
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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 anti-angiogenic function.
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