The Angiogenic Inhibitor Long Pentraxin PTX3 Forms an Asymmetric Octamer with Two Binding Sites for FGF2
The Angiogenic Inhibitor Long Pentraxin PTX3 Forms an Asymmetric Octamer with Two Binding Sites for FGF2
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DOI：
10.1074/jbc.m109.085639
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发表时间：
2010-06-04
影响因子：
4.8
通讯作者：
Day, Anthony J.
中科院分区：
文献类型：
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作者：
Inforzato, Antonio;Baldock, Clair;Day, Anthony J.
炎症相关的长五聚蛋白PTX 3在先天免疫、女性生育力和血管生物学中起关键作用（例如，它抑制FGF 2（成纤维细胞生长因子2）介导的血管生成）。PTX 3由多个原聚体组成，每个原聚体由不同的N-和C-末端结构域组成;然而，尚不清楚这些结构域是如何组织的或对其功能特性有何贡献。在这里，生物物理分析表明，PTX 3是由八个相同的原聚体，通过二硫键，形成一个细长的和不对称的，分子与两个不同大小的结构域通过茎相互连接。原聚体的N-末端区域提供了这种四元结构的主要结构决定因素，支持形成二硫键连接的四聚体和二聚体的二聚体（非共价四聚体），引起分子的不对称性。此外，PTX 3八聚体显示含有两个FGF 2结合位点，其中四聚体充当配体识别中的功能单元。因此，这些研究提供了PTX 3寡聚体的统一模型，解释了其四级结构以及其抗血管生成功能如何需要这一点。
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.