Structural specializations of A2, a force-sensing domain in the ultralarge vascular protein von Willebrand factor
Structural specializations of A2, a force-sensing domain in the ultralarge vascular protein von Willebrand factor
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DOI：
10.1073/pnas.0903679106
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发表时间：
2009-06-09
影响因子：
11.1
通讯作者：
Springer, Timothy A.
中科院分区：
文献类型：
--
作者：
Zhang, Qing;Zhou, Yan-Feng;Springer, Timothy A.
血管性血友病因子（VWF）多联体的长度与止血效力相关。在血浆中分泌后，长度由A2结构域的流体动力学剪切力依赖性解折叠调节，然后由特异性蛋白酶切割。A2结构域的1.9埃晶体结构证明了这种剪切传感器功能的进化适应性。在VWF A（VWA）结构域中独特的是，A2含有代替α 4螺旋的环和顺式脯氨酸。中心β 4链包装不良，具有多个侧链旋转异构体。Tyr-Met切割位点埋在中心疏水核心的β 4链中，Tyr在结构上连接至C末端α 6螺旋。α 6-螺旋以2个Cys残基结束，Cys残基通过一个不寻常的邻位二硫键连接，该二硫键埋在疏水口袋中。这些特征可以缩小展开发生的力范围，并且还可以减慢重折叠。血管性血友病的突变，可能会降低A2展开的力，被结构照亮。
The lengths of von Willebrand factor (VWF) concatamers correlate with hemostatic potency. After secretion in plasma, length is regulated by hydrodynamic shear force-dependent unfolding of the A2 domain, which is then cleaved by a specific protease. The 1.9-angstrom crystal structure of the A2 domain demonstrates evolutionary adaptations to this shear sensor function. Unique among VWF A (VWA) domains, A2 contains a loop in place of the alpha 4 helix, and a cis-proline. The central beta 4-strand is poorly packed, with multiple side-chain rotamers. The Tyr-Met cleavage site is buried in the beta 4-strand in the central hydrophobic core, and the Tyr structurally links to the C-terminal alpha 6-helix. The alpha 6-helix ends in 2 Cys residues that are linked by an unusual vicinal disulfide bond that is buried in a hydrophobic pocket. These features may narrow the force range over which unfolding occurs and may also slow refolding. Von Willebrand disease mutations, which presumably lower the force at which A2 unfolds, are illuminated by the structure.