A naturally occurring extracellular alpha-beta clasp contributes to stabilization of beta3 integrins in a bent, resting conformation.
A naturally occurring extracellular alpha-beta clasp contributes to stabilization of beta3 integrins in a bent, resting conformation.
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DOI：
10.1021/bi8015108
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发表时间：
2008-10
期刊：
影响因子：
2.9
通讯作者：
Anthony N. Vomund;S. Stuhlsatz-Krouper;J. Dimitry;Yuhua Song;W. Frazier
中科院分区：
文献类型：
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作者：
Anthony N. Vomund;S. Stuhlsatz-Krouper;J. Dimitry;Yuhua Song;W. Frazier
控制α IIb β 3和α v β 3整合素活化对心血管稳态至关重要。干扰整合素α和β亚基在其跨膜和胞质区域中的缔合的突变激活整合素异二聚体，表明低亲和力或“关闭”构象是默认状态，可能对应于在α v β 3的晶体结构中看到的弯曲构象。在该弯曲结构中，α v（301-308）和β 3（560-567）的片段并置。在这里，我们提供的证据表明，这些地区的α v/α IIb和β 3功能作为一种新的细胞外扣抑制激活。代表α IIb和β 3 clasp区域的合成肽促进整合素活化，如通过细胞粘附、细胞铺展和三种β 3 LIBS抗体的表位暴露所判断的。α v或β 3的卡环区域的突变导致组成型活化的整合素，证实了细胞外卡环在抑制整合素活化中的作用。分子动力学模拟的α V β 3结构产生一个完善的模型α V β 3扣和激活突变的影响提供了合理的解释。
Control of alphaIIb beta3 and alphav beta3 integrin activation is critical for cardiovascular homeostasis. Mutations that perturb association of integrin alpha and beta subunits in their transmembrane and cytoplasmic regions activate the integrin heterodimer, suggesting that a low-affinity or "off" conformation is the default state, likely corresponding to the bent conformation seen in the crystal structure of alphav beta3. In this bent structure, a segment of alphav (301-308) and beta3 (560-567) are juxtaposed. Here we provide evidence that these regions of alphav/alphaIIb and beta3 function as a novel extracellular clasp to restrain activation. Synthetic peptides representing the alphaIIb and beta3 clasp regions promote integrin activation as judged by cell adhesion, cell spreading, and exposure of epitopes for three beta3 LIBS antibodies. Mutation of the clasp region of alphav or beta3 results in a constitutively activated integrin, confirming the role of the extracellular clasp in restraining integrin activation. Molecular dynamics simulations of the alphav beta3 structure yield a refined model for the alphav beta3 clasp and provide plausible explanations for the effects of the activating mutations.