Zhang Qing, Zhou Yan-Feng, Zhang Cheng-Zhong, Zhang Xiaohui, Lu Chafen, Springer Timothy A
Immune Disease Institute, Children's Hospital Boston and Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9226-31. doi: 10.1073/pnas.0903679106. Epub 2009 May 21.
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-A 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 alpha4 helix, and a cis-proline. The central beta4-strand is poorly packed, with multiple side-chain rotamers. The Tyr-Met cleavage site is buried in the beta4-strand in the central hydrophobic core, and the Tyr structurally links to the C-terminal alpha6-helix. The alpha6-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.
血管性血友病因子（VWF）多聚体的长度与止血效力相关。在血浆中分泌后，其长度通过A2结构域依赖流体动力剪切力的展开来调节，随后被一种特定蛋白酶切割。A2结构域的1.9埃晶体结构展示了对这种剪切传感器功能的进化适应性。在VWF A（VWA）结构域中独一无二的是，A2含有一个取代α4螺旋的环和一个顺式脯氨酸。中央β4链堆积不佳，有多个侧链旋转异构体。酪氨酸-甲硫氨酸切割位点埋在中央疏水核心的β4链中，酪氨酸在结构上与C端α6螺旋相连。α6螺旋末端有两个半胱氨酸残基，它们通过一个埋在疏水口袋中的不寻常邻位二硫键相连。这些特征可能会缩小发生展开的力的范围，也可能会减缓重新折叠。血管性血友病的突变可能会降低A2展开所需的力，该结构揭示了这些突变。
