The Evolution of Thrombospondins and Their Ligand-Binding Activities
The Evolution of Thrombospondins and Their Ligand-Binding Activities
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DOI：
10.1093/molbev/msq107
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发表时间：
2010-09-01
影响因子：
10.7
通讯作者：
Adams, Josephine C.
中科院分区：
文献类型：
--
作者：
Bentley, Amber A.;Adams, Josephine C.
细胞外基质（ECM）是一个复杂的多蛋白网络，在后生动物的组织完整性和细胞间信号传导中具有重要作用。血小板反应蛋白（TSPs）是细胞外的钙结合糖蛋白，在哺乳动物的血管生成、血管生物学、结缔组织、免疫反应和突触发生中具有重要的生物学作用。人们对这些复杂功能特性的演化了解甚少。我们在此报告了TSPs及其配体结合能力的演化，这是通过对代表后生动物主要门的物种进行比较基因组学研究以及对基础后口动物的非经典TSPs的寡聚化特性进行实验分析得出的。单体、二聚体、三聚体和五聚体TSPs是通过涉及卷曲螺旋结构域或氨基末端不同结构域的获得、丢失或修饰的独立进化事件而产生的。在进化过程中单体形式的相对短暂性暗示了TSPs的C末端区域多价性的生物学重要性。大多数原口动物具有一个编码五聚体TSP的单一TSP基因。五聚体形式也存在于后口动物中，在后口动物起源时的基因重复以及脊椎动物谱系中的基因丢失和进一步的基因重复事件产生了不同的形式和新的结构域架构。对哺乳动物TSPs的主要配体的平行分析表明，许多结合活性是新功能，代表了后口动物谱系中的协同进化创新或诸如CD36等古老分子的新功能。形成鲜明对比的是，广泛保守的能力包括与硫酸乙酰肝素糖胺聚糖、纤维状胶原蛋白或依赖RGD的整合素的结合。这些发现确定TSPs是后生动物细胞外相互作用系统的基本组成部分，从而影响了对ECM网络演化的理解。TSPs在与ECM成分或PS2分支整合素结合方面广泛保守的活性将与在合成细胞外基质或组织工程中使用TSPs相关。相比之下，脊椎动物TSPs的新功能可能包括适合作为治疗靶点的相互作用，而不会普遍破坏ECM。
The extracellular matrix (ECM) is a complex, multiprotein network that has essential roles in tissue integrity and intercellular signaling in the metazoa. Thrombospondins (TSPs) are extracellular, calcium-binding glycoproteins that have biologically important roles in mammals in angiogenesis, vascular biology, connective tissues, immune response, and synaptogenesis. The evolution of these complex functional properties is poorly understood. We report here on the evolution of TSPs and their ligand-binding capacities, from comparative genomics of species representing the major phyla of metazoa and experimental analyses of the oligomerization properties of noncanonical TSPs of basal deuterostomes. Monomeric, dimeric, trimeric, and pentameric TSPs have arisen through separate evolutionary events involving gain, loss, or modification of a coiled-coil domain or distinct domains at the amino-terminus. The relative transience of monomeric forms under evolution implicates a biological importance for multivalency of the C-terminal region of TSPs. Most protostomes have a single TSP gene encoding a pentameric TSP. The pentameric form is also present in deuterostomes, and gene duplications at the origin of deuterostomes and gene loss and further gene duplication events in the vertebrate lineage gave rise to distinct forms and novel domain architectures. Parallel analysis of the major ligands of mammalian TSPs revealed that many binding activities are neofunctions representing either coevolutionary innovations in the deuterostome lineage or neofunctions of ancient molecules such as CD36. Contrasting widely conserved capacities include binding to heparan glycosaminoglycans, fibrillar collagen, or RGD-dependent integrins. These findings identify TSPs as fundamental components of the extracellular interaction systems of metazoa and thus impact understanding of the evolution of ECM networks. The widely conserved activities of TSPs in binding to ECM components or PS2 clade integrins will be relevant to use of TSPs in synthetic extracellular matrices or tissue engineering. In contrast, the neofunctions of vertebrate TSPs likely include interactions suitable for therapeutic targeting without general disruption of ECM.