Tan Kemin, Lawler Jack
Midwest Center for Structural Genomics and Structural Biology Center, Biosciences Division, Argonne National Laboratory, Argonne, IL 60439, USA.
BMC Struct Biol. 2011 May 10;11:22. doi: 10.1186/1472-6807-11-22.
F-spondin is a multi-domain extracellular matrix (ECM) protein and a contact-repellent molecule that directs axon outgrowth and cell migration during development. The reelin_N domain and the F-spondin domain (FS domain) comprise a proteolytic fragment that interacts with the cell membrane and guides the projection of commissural axons to floor plate. The FS domain is found in F-spondins, mindins, M-spondin and amphiF-spondin.
We present the crystal structure of human F-spondin FS domain at 1.95Å resolution. The structure reveals a Ca2+-binding C2 domain variant with an 8-stranded antiparallel β-sandwich fold. Though the primary sequences of the FS domains of F-spondin and mindin are less than 36% identical, their overall structures are very similar. The unique feature of F-spondin FS domain is the presence of three disulfide bonds associated with the N- and C-termini of the domain and a highly conserved N-linked glycosylation site. The integrin-binding motif found in mindin is not conserved in the F-spondin FS domain.
The structure of the F-spondin FS domain completes the structural studies of the multiple-domain ECM molecule. The homology of its core structure to a common Ca2+- and lipid-binding C2 domain suggests that the F-spondin FS domain may be responsible for part of the membrane targeting of F-spondin in its regulation of axon development. The structural properties of the FS domain revealed in this study pave the way for further exploration into the functions of F-spondin.
F-spondin是一种多结构域的细胞外基质（ECM）蛋白，是一种接触排斥分子，在发育过程中指导轴突生长和细胞迁移。reelin_N结构域和F-spondin结构域（FS结构域）构成一个蛋白水解片段，该片段与细胞膜相互作用并引导连合轴突向底板投射。FS结构域存在于F-spondin、mindin、M-spondin和两栖F-spondin中。
我们展示了人F-spondin FS结构域在1.95Å分辨率下的晶体结构。该结构揭示了一种具有8股反平行β折叠的结合Ca2+的C2结构域变体。尽管F-spondin和mindin的FS结构域的一级序列相似度不到36%，但其整体结构非常相似。F-spondin FS结构域的独特特征是存在与该结构域的N端和C端相关的三个二硫键以及一个高度保守的N-连接糖基化位点。在mindin中发现的整合素结合基序在F-spondin FS结构域中并不保守。
F-spondin FS结构域的结构完成了对多结构域ECM分子的结构研究。其核心结构与常见的结合Ca2+和脂质的C2结构域的同源性表明，F-spondin FS结构域可能在其对轴突发育的调节中负责F-spondin的部分膜靶向作用。本研究揭示的FS结构域的结构特性为进一步探索F-spondin的功能铺平了道路。
