Mechanism for KRIT1 release of ICAP1-mediated suppression of integrin activation.
Mechanism for KRIT1 release of ICAP1-mediated suppression of integrin activation.
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DOI：
10.1016/j.molcel.2012.12.005
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发表时间：
2013-02-21
期刊：
影响因子：
16
通讯作者：
Boggon, Titus J.
中科院分区：
文献类型：
--
作者：
Liu, Weizhi;Draheim, Kyle M.;Zhang, Rong;Calderwood, David A.;Boggon, Titus J.
KRIT1(Krev/Rap1相互作用陷阱-1)突变见于约40%的常染色体显性遗传性脑海绵状畸形(CCM)，该疾病的发病率高达0.5%。我们发现，KRIT1通过拮抗β-1(整合素细胞质相关蛋白-1)介导的“由内向外”的激活调控，发挥了整合素1整合素激活的开关作用。我们给出了KRIT1与ICAP1和ICAP1与整合素β1胞质尾巴的共晶结构，其分辨率分别为2.54？和3.0？(I/σi=2的分辨率分别为2.75？和3.0？)。我们发现KRIT1通过双齿表面与ICAP1结合，KRIT1与整合素β1直接竞争结合ICAP1，KRIT1通过该位点拮抗ICAP1调节的整合素激活。我们还发现KRIT1含有一个N-末端的Nudex结构域，位于以前被指定为非结构化的区域。因此，我们对整合素的调控和CCM相关的KRIT1功能提供了新的见解。
KRIT1 (Krev/Rap1 Interaction Trapped-1) mutations are observed in ~40% of autosomal dominant cerebral cavernous malformations (CCM), a disease occurring in up to 0.5% of the population. We show that KRIT1 functions as a switch for β1 integrin activation by antagonizing ICAP1 (Integrin Cytoplasmic Associated Protein-1)-mediated modulation of “inside-out” activation. We present co-crystal structures of KRIT1 with ICAP1 and ICAP1 with integrin β1 cytoplasmic tail to 2.54 Å and 3.0 Å resolution (the resolutions at which I/σI = 2 are 2.75 Å and 3.0 Å, respectively). We find that KRIT1 binds ICAP1 by a bidentate surface, KRIT1 directly competes with integrin β1 to bind ICAP1, and that KRIT1 antagonizes ICAP1-modulated integrin activation using this site. We also find that KRIT1 contains an N-terminal Nudix domain, in a region previously designated as unstructured. We therefore provide new insights to integrin regulation and CCM-associated KRIT1 function.
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