Identification of Vascular Endothelial Growth Factor Receptor-binding Protein in the Venom of Eastern Cottonmouth
Identification of Vascular Endothelial Growth Factor Receptor-binding Protein in the Venom of Eastern Cottonmouth
复制标题
东部棉口蛇毒液中血管内皮生长因子受体结合蛋白的鉴定
DOI：
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发表时间：
2005
影响因子：
4.8
通讯作者：
T. Morita
中科院分区：
文献类型：
--
作者：
Y. Yamazaki;Y. Matsunaga;Yuta Nakano;T. Morita
血管内皮生长因子（VEGF165）及其受体KDR（激酶插入结构域受体）是血管形成的主要调节因子。本文报道了从东部水腹蛇（Agkistrodon piscivorus piscivorus）毒液中分离出的一种kdr结合蛋白。序列分析显示，分离的kdr结合蛋白（指定KDR-bp）与Lys49-磷脂酶A2 （Lys49PLA2）相同，这是一种具有强肌毒性的无活性PLA2同源物，其中Lys49取代了Asp49，这是结合必需辅因子Ca2+的关键残基。KDR-bp以亚纳摩尔的亲和力结合到KDR的细胞外结构域。KDR-bp也在较小程度上与Flt-1和IgG结合，但不与其他具有类似免疫球蛋白样结构域的受体结合，如血小板源性生长因子受体α。KDR-bp与KDR的相互作用被VEGF165阻断，KDR-bp特异性抑制VEGF165刺激的内皮细胞增殖，表明KDR-bp是KDR的拮抗配体。从另一种蛇毒中发现Lys49PLA2s与KDR-bp具有相似的受体结合特性。这是第一个证明外源性因子拮抗VEGF及其受体系统的报道。我们的观察结果为蛇毒Lys49PLA2s肌毒活性的未知分子机制提供了进一步的见解。此外，KDR-bp将为研究KDR的结构和功能提供有价值的工具，例如在骨骼肌细胞上表达的KDR。
Vascular endothelial growth factor (VEGF165) and its receptor KDR (kinase insert domain-containing receptor) are central regulators of blood vessel formation. We herein report a KDR-binding protein we have isolated in the venom of eastern cottonmouth (Agkistrodon piscivorus piscivorus). Sequence analysis revealed the isolated KDR-binding protein (designated KDR-bp) is identical to Lys49-phosholipase A2 (Lys49PLA2), an inactive PLA2 homologue with strong myotoxicity, in which Lys49 substitutes Asp49, a key residue for binding the essential cofactor Ca2+. KDR-bp binds to the extracellular domain of KDR with subnanomolar affinity. KDR-bp also binds to a lesser extent with Flt-1 and IgG but not to other receptors with similar immunoglobulin-like domain structures such as platelet-derived growth factor receptor α. The interaction between KDR-bp and KDR was blocked by VEGF165, and KDR-bp specifically inhibited VEGF165-stimulated endothelial cell proliferation, indicating KDR-bp is an antagonistic ligand for KDR. Lys49PLA2s from another snake venom were found to exhibit similar receptor binding properties to KDR-bp. This is the first report to demonstrate that an exogenous factor antagonizes VEGF and its receptor system. Our observation offers further insight into the as yet unknown molecular mechanism of myotoxic activity of snake venom Lys49PLA2s. Furthermore, KDR-bp would make a valuable tool for studying the structure and function of KDR, such as that expressed on skeletal muscle cells.
影响因子：
15.9
作者：
Dias, S;Hattori, K;Rafii, S
通讯作者：
Rafii, S
影响因子：
56.9
作者：
DEVRIES, C;ESCOBEDO, JA;WILLIAMS, LT
通讯作者：
WILLIAMS, LT
影响因子：
20.3
作者：
Dias, S;Shmelkov, SV;Rafii, S
通讯作者：
Rafii, S