Extracellular Regulation of Bone Morphogenetic Protein Activity by the Microfibril Component Fibrillin-1.
Extracellular Regulation of Bone Morphogenetic Protein Activity by the Microfibril Component Fibrillin-1.
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DOI：
10.1074/jbc.m115.704734
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发表时间：
2016-06-10
期刊：
影响因子：
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通讯作者：
Sengle G
中科院分区：
文献类型：
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作者：
Wohl AP;Troilo H;Collins RF;Baldock C;Sengle G
自从发现骨形态发生蛋白（BMP）作为可从骨基质中提取的多能细胞因子以来，已经推测BMP靶向细胞外基质（ECM）如何调节其生物利用度。了解这些过程是至关重要的阐明结缔组织疾病的病理机制，其特征在于ECM缺乏和生长因子失调。在这里，我们提供了一个新的BMP靶向和螯合机制，是由ECM分子的骨形成蛋白-1控制的证据。我们目前的BMP-7前结构域生长因子复合物的纳米级结构，使用电子显微镜，小角X射线散射，和圆二色光谱，表明它假定一个开放的V型结构时，它是生物活性的。然而，在结合到BMP-7复合物1时，BMP-7复合物呈现为闭环形状，这也赋予生长因子潜伏期，如通过生物活性测量所证明的。BMP-7前结构域变体用于绘制前结构域-生长因子和前结构域-前结构域结合的关键表位。总之，这些数据表明，在前结构域结合到BMP-1后，BMP-7复合物经历构象变化，其拒绝BMP受体接近生长因子。
Since the discovery of bone morphogenetic proteins (BMPs) as pluripotent cytokines extractable from bone matrix, it has been speculated how targeting of BMPs to the extracellular matrix (ECM) modulates their bioavailability. Understanding these processes is crucial for elucidating pathomechanisms of connective tissue disorders characterized by ECM deficiency and growth factor dysregulation. Here, we provide evidence for a new BMP targeting and sequestration mechanism that is controlled by the ECM molecule fibrillin-1. We present the nanoscale structure of the BMP-7 prodomain-growth factor complex using electron microscopy, small angle x-ray scattering, and circular dichroism spectroscopy, showing that it assumes an open V-like structure when it is bioactive. However, upon binding to fibrillin-1, the BMP-7 complex is rendered into a closed ring shape, which also confers latency to the growth factor, as demonstrated by bioactivity measurements. BMP-7 prodomain variants were used to map the critical epitopes for prodomain-growth factor and prodomain-prodomain binding. Together, these data show that upon prodomain binding to fibrillin-1, the BMP-7 complex undergoes a conformational change, which denies access of BMP receptors to the growth factor.