Structure of three tandem filamin domains reveals auto-inhibition of ligand binding
Structure of three tandem filamin domains reveals auto-inhibition of ligand binding
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DOI：
10.1038/sj.emboj.7601827
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发表时间：
2007-09-05
期刊：
影响因子：
11.4
通讯作者：
Ylaenne, Jari
中科院分区：
文献类型：
--
作者：
Lad, Yatish;Kiema, Tiila;Ylaenne, Jari
人丝蛋白是大的肌动蛋白交联蛋白，由一个n端肌动蛋白结合结构域和24个igg样结构域（igfln）组成，与许多跨膜受体和细胞质信号蛋白相互作用。本文报道了人丝蛋白a （IgFLNa19-21）的一个三域片段的2.5A分辨率结构。该结构揭示了一个意想不到的结构域排列，IgFLNa20部分展开，使IgFLNa21靠近IgFLNa19。值得注意的是，IgFLNa20的n端形成一条β链，与IgFLNa21的CD面结合，并占据整合素粘附受体的结合位点。IgFLNa20-IgFLNa21相互作用的破坏增强了丝蛋白与整合素β尾的结合。其他IgFLN结构域的结构和功能分析表明，邻近IgFLN结构域的自抑制可能是控制丝蛋白-配体相互作用的一般机制。这可以解释丝蛋白剪接变异体整合素结合的增加，并提供了配体结合可能影响丝蛋白结构的机制。
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 2.5A 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.