Intermolecular interactions of thrombospondins drive their accumulation in extracellular matrix.
Intermolecular interactions of thrombospondins drive their accumulation in extracellular matrix.
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DOI：
10.1091/mbc.e14-05-0996
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发表时间：
2015-07-15
影响因子：
3.3
通讯作者：
Adams JC
中科院分区：
文献类型：
--
作者：
Kim DJ;Christofidou ED;Keene DR;Hassan Milde M;Adams JC
发现了反式分子间相互作用的新机制，血小板反应蛋白分子通过该机制在细胞外基质内以点状积累。该过程依赖于血小板反应蛋白 L 型凝集素结构域上的一个新颖的、保守的、表面暴露的位点。血小板反应蛋白参与成人组织稳态中组织组织的许多方面，其失调会导致纤维化和肿瘤进展等病理过程。血小板反应蛋白作为离散点掺入细胞外基质（ECM）已在各种组织和细胞生物学背景中得到记录，但其潜在机制仍知之甚少。我们发现 Thbs1−/− 小鼠的多个组织中的胶原纤维杂乱无章。在研究血小板反应蛋白如何保留在 ECM 中并从而影响 ECM 组织时，我们发现细胞源性 ECM 中血小板反应蛋白-1 或血小板反应蛋白-5 点的积累是由血小板反应蛋白 L 型凝集素结构域上的一个新的、保守的、表面暴露的位点控制的。该位点通过反式分子间相互作用将血小板反应蛋白分子招募到 ECM 中。该机制不依赖于纤连蛋白，可以在细胞外发生，并且在体外被证明是直接的。反式分子间相互作用也可以是异型的，例如血小板反应蛋白-1 和血小板反应蛋白-5 之间的相互作用。这些数据确定了浓度依赖性、分子间“基质捕获”的新概念，作为一种保守机制，控制 ECM 中血小板反应蛋白的积累，从而控制其功能。
A novel mechanism of intermolecular interactions in trans is identified by which thrombospondin molecules accumulate as puncta within the extracellular matrix. This process depends on a novel, conserved, surface-exposed site on the thrombospondin L-type lectin domain. Thrombospondins participate in many aspects of tissue organization in adult tissue homeostasis, and their dysregulation contributes to pathological processes such as fibrosis and tumor progression. The incorporation of thrombospondins into extracellular matrix (ECM) as discrete puncta has been documented in various tissue and cell biological contexts, yet the underlying mechanisms remain poorly understood. We find that collagen fibrils are disorganized in multiple tissues of Thbs1−/− mice. In investigating how thrombospondins become retained within ECM and thereby affect ECM organization, we find that accumulation of thrombospondin-1 or thrombospondin-5 puncta within cell-derived ECM is controlled by a novel, conserved, surface-exposed site on the thrombospondin L-type lectin domain. This site acts to recruit thrombospondin molecules into ECM by intermolecular interactions in trans. This mechanism is fibronectin independent, can take place extracellularly, and is demonstrated to be direct in vitro. The trans intermolecular interactions can also be heterotypic—for example, between thrombospondin-1 and thrombospondin-5. These data identify a novel concept of concentration-dependent, intermolecular “matrix trapping” as a conserved mechanism that controls the accumulation and thereby the functionality of thrombospondins in ECM.