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首页> 美国卫生研究院文献>The Journal of Biological Chemistry >Sizzled Is Unique among Secreted Frizzled-related Proteins for Its Ability to Specifically Inhibit Bone Morphogenetic Protein-1 (BMP-1)/Tolloid-like Proteinases
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Sizzled Is Unique among Secreted Frizzled-related Proteins for Its Ability to Specifically Inhibit Bone Morphogenetic Protein-1 (BMP-1)/Tolloid-like Proteinases

机译：Sizzled在分泌的卷曲相关蛋白中具有独特的作用因为它能够特异性抑制骨形态发生蛋白1（BMP-1）/类瘤样蛋白酶。

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BMP-1/tolloid-like proteinases (BTPs) are major enzymes involved in extracellular matrix assembly and activation of bioactive molecules, both growth factors and anti-angiogenic molecules. Although the control of BTP activity by several enhancing molecules is well established, the possibility that regulation also occurs through endogenous inhibitors is still debated. Secreted frizzled-related proteins (sFRPs) have been studied as possible candidates, with highly contradictory results, after the demonstration that sizzled, a sFRP found in Xenopus and zebrafish, was a potent inhibitor of Xenopus and zebrafish tolloid-like proteases. In this study, we demonstrate that mammalian sFRP-1, -2, and -4 do not modify human BMP-1 activity on several of its known substrates including procollagen I, procollagen III, pN-collagen V, and prolysyl oxidase. In contrast, Xenopus sizzled appears as a tight binding inhibitor of human BMP-1, with a Ki of 1.5 ± 0.5 nm, and is shown to strongly inhibit other human tolloid isoforms mTLD and mTLL-1. Because sizzled is the most potent inhibitor of human tolloid-like proteinases known to date, we have studied its mechanism of action in detail and shown that the frizzled domain of sizzled is both necessary and sufficient for inhibitory activity and that it acts directly on the catalytic domain of BMP-1. Residues in sizzled required for inhibition include Asp-92, which is shared by sFRP-1 and -2, and also Phe-94, Ser-43, and Glu-44, which are specific to sizzled, thereby providing a rational basis for the absence of inhibitory activity of human sFRPs.
机译：BMP-1 /类Tolloid蛋白酶（BTP）是参与细胞外基质组装和生物活性分子（包括生长因子和抗血管生成分子）活化的主要酶。尽管已经很好地确定了通过几种增强分子控制BTP活性的方法，但仍在讨论通过内源性抑制剂进行调节的可能性。已证明分泌的卷曲相关蛋白（sFRPs）是可能的候选物，其结果相互矛盾，在证明发炎后，证明在非洲爪蟾和斑马鱼中发现的一种sFRP是爪蟾和斑马鱼类弓形蛋白酶的有效抑制剂。在这项研究中，我们证明哺乳动物sFRP-1，-2和-4不会在几种已知底物（包括胶原蛋白I，胶原蛋白III，pN胶原蛋白V和脯氨酰氧化酶）上修饰人BMP-1活性。相反，非洲爪蟾似乎是人BMP-1的紧密结合抑制剂，Ki为1.5±0.5 nm，并显示出强烈抑制其他人类同种型mTLD和mTLL-1的作用。由于sizzled是迄今已知的最有效的人类tolloid样蛋白酶抑制剂，因此我们已详细研究了其作用机理，并显示sizzled的frizzled域对于抑制活性既必要又充分，并且直接作用于催化BMP-1的结构域。抑制所需的铁锈残渣包括sFRP-1和-2共有的Asp-92，以及铁锈特异性的Phe-94，Ser-43和Glu-44，从而为铁锈提供了合理的依据。没有人sFRP的抑制活性。

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