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首页> 外文期刊>Journal of Molecular Biology >Effect of C-terminal sequence on competitive semaphorin binding to neuropilin-1
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Effect of C-terminal sequence on competitive semaphorin binding to neuropilin-1

机译：C末端序列对竞争信号量与Neuropilin-1结合的影响

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摘要

Neuropilins (Nrp) are type I transmembrane proteins that function as receptors for vascular endothelial growth factor (VEGF) and class III Semaphorin (Sema3) ligand families. Sema3s function as potent endogenous angiogenesis inhibitors but require proteolytically processing by furin to compete with VEGF for Nrp binding. This processing liberates a C-terminal arginine (CR) that is necessary for binding to the b1 domain of Nrp, a common feature shared by Nrp ligands. The CR is necessary but not sufficient for potent Nrp inhibition, and the role of upstream residues is unknown. We demonstrate that the second-to-last residue (C-1), immediately upstream of the CR, plays a significant role in controlling competitive ligand binding by orienting the C-terminus for productive Nrp binding. With the use of a peptide library derived from Sema3F, C-1 residues that preferentially adopt an extended bound-like conformation, including proline and β-branched amino acids, were found to produce the most avid competitors. Consistent with this, analysis of the binding thermodynamics revealed that more favorable entropy is responsible for the observed binding enhancement of C-1 proline. We further tested the effect of the C-1 residue on Sema3F processing by furin and found an inverse relationship between processing and inhibitory potency. Analysis of all Sema3 family members reveals two non-equivalent furin processing sites differentiated by the presence of either a C-1 proline or a C-1 arginine and resulting in up to a 40-fold difference in potency. These data reveal a novel regulatory mechanism of Sema3 activity and define a fundamental mechanism for preferential Nrp binding.
机译：Neuropilins（Nrp）是I型跨膜蛋白，可作为血管内皮生长因子（VEGF）和III类Semaphorin（Sema3）配体家族的受体。 Sema3s充当有效的内源性血管生成抑制剂，但需要弗林蛋白酶进行蛋白水解加工才能与VEGF竞争Nrp结合。此过程释放出一个C端精氨酸（CR），这是结合Nrp的b1域所必需的，Nrp是Nrp配体的共同特征。对于有效的Nrp抑制来说，CR是必需的，但还不足以发挥作用，并且上游残基的作用尚不清楚。我们证明，倒数第二个残基（C-1），紧邻CR的上游，通过定向C末端用于生产性Nrp结合，在控制竞争性配体结合中起重要作用。通过使用衍生自Sema3F的肽库，发现优先采用扩展的结合样构象的C-1残基（包括脯氨酸和β-支链氨基酸）产生了最激烈的竞争者。与此相一致，对结合热力学的分析表明，更有利的熵负责观察到的C-1脯氨酸的结合增强。我们进一步测试了C-1残基对弗林蛋白酶对Sema3F加工的影响，并发现加工与抑制效能之间存在反比关系。对所有Sema3家族成员的分析显示，存在两个不等价的弗林蛋白酶加工位点，这些位点因存在C-1脯氨酸或C-1精氨酸而有所区别，并导致效能差异高达40倍。这些数据揭示了Sema3活性的新型调节机制，并定义了优先Nrp绑定的基本机制。

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