Lad Yatish, Kiema Tiila, Jiang Pengju, Pentikäinen Olli T, Coles Charlotte H, Campbell Iain D, Calderwood David A, Ylänne Jari
Department of Pharmacology and Interdepartmental Program in Vascular Biology and Transplantation, Yale University School of Medicine, New Haven, CT 06520, USA.
EMBO J. 2007 Sep 5;26(17):3993-4004. doi: 10.1038/sj.emboj.7601827. Epub 2007 Aug 9.
Human filamins are large actin-crosslinking proteins composed of an N-terminal actin-binding domain followed by 24 Ig-like domains (IgFLNs), which interact with numerous transmembrane receptors and cytosolic signaling proteins. Here we report the 2.5 A resolution structure of a three-domain fragment of human filamin A (IgFLNa19-21). The structure reveals an unexpected domain arrangement, with IgFLNa20 partially unfolded bringing IgFLNa21 into close proximity to IgFLNa19. Notably the N-terminus of IgFLNa20 forms a beta-strand that associates with the CD face of IgFLNa21 and occupies the binding site for integrin adhesion receptors. Disruption of this IgFLNa20-IgFLNa21 interaction enhances filamin binding to integrin beta-tails. Structural and functional analysis of other IgFLN domains suggests that auto-inhibition by adjacent IgFLN domains may be a general mechanism controlling filamin-ligand interactions. This can explain the increased integrin binding of filamin splice variants and provides a mechanism by which ligand binding might impact filamin structure.
人细丝蛋白是一种大型肌动蛋白交联蛋白，由一个N端肌动蛋白结合结构域和其后的24个免疫球蛋白样结构域（IgFLNs）组成，这些结构域可与众多跨膜受体和胞质信号蛋白相互作用。在此，我们报道了人细丝蛋白A（IgFLNa19 - 21）的一个三结构域片段的2.5埃分辨率结构。该结构揭示了一种意想不到的结构域排列方式，其中IgFLNa20部分展开，使IgFLNa21与IgFLNa19紧密相邻。值得注意的是，IgFLNa20的N端形成一条β链，与IgFLNa21的CD面结合，并占据整合素黏附受体的结合位点。这种IgFLNa20 - IgFLNa21相互作用的破坏增强了细丝蛋白与整合素β尾的结合。对其他IgFLN结构域的结构和功能分析表明，相邻IgFLN结构域的自抑制可能是控制细丝蛋白 - 配体相互作用的一种普遍机制。这可以解释细丝蛋白剪接变体整合素结合增加的现象，并提供了一种配体结合可能影响细丝蛋白结构的机制。
