Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
Structure. 2013 Oct 8;21(10):1743-56. doi: 10.1016/j.str.2013.08.004. Epub 2013 Sep 12.
The human extracellular matrix glycoprotein fibrillin-1 is the primary component of the 10- to 12-nm-diameter microfibrils, which perform key structural and regulatory roles in connective tissues. Relatively little is known about the molecular mechanisms of fibrillin assembly into microfibrils. Studies using recombinant fibrillin fragments indicate that an interaction between the N- and C-terminal regions drives head-to-tail assembly. Here, we present the structure of a fibrillin N-terminal fragment comprising the fibrillin unique N-terminal (FUN) and the first three epidermal growth factor (EGF)-like domains (FUN-EGF3). Two rod-like domain pairs are separated by a short, flexible linker between the EGF1 and EGF2 domains. We also show that the binding site for the C-terminal region spans multiple domains and overlaps with a heparin interaction site. These data suggest that heparan sulfate may sequester fibrillin at the cell surface via FUN-EGF3 prior to aggregation of the C terminus, thereby regulating microfibril assembly.
人类细胞外基质糖蛋白原纤维蛋白-1 是 10 至 12nm 直径微纤维的主要成分，在结缔组织中发挥关键的结构和调节作用。关于原纤维蛋白组装成微纤维的分子机制知之甚少。使用重组原纤维蛋白片段的研究表明，N-和 C-末端区域之间的相互作用驱动头尾组装。在这里，我们展示了一个原纤维蛋白 N-末端片段的结构，该片段包含原纤维蛋白独特的 N-末端（FUN）和前三个表皮生长因子（EGF）样结构域（FUN-EGF3）。两个杆状结构域对由 EGF1 和 EGF2 结构域之间的短柔性接头隔开。我们还表明，C-末端区域的结合位点跨越多个结构域，并与肝素相互作用位点重叠。这些数据表明，肝素硫酸盐可能通过 FUN-EGF3 将原纤维蛋白固定在细胞表面，然后再聚集 C 末端，从而调节微纤维的组装。
