Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
Mol Cell. 2013 Feb 21;49(4):719-29. doi: 10.1016/j.molcel.2012.12.005. Epub 2013 Jan 11.
KRIT1 (Krev/Rap1 Interaction Trapped-1) mutations are observed in ∼40% of autosomal-dominant cerebral cavernous malformations (CCMs), 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 cocrystal structures of KRIT1 with ICAP1 and ICAP1 with integrin β1 cytoplasmic tail to 2.54 and 3.0 Å resolution (the resolutions at which I/σI = 2 are 2.75 and 3.0 Å, respectively). We find that KRIT1 binds ICAP1 by a bidentate surface, that 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 insights to integrin regulation and CCM-associated KRIT1 function.
KRIT1（Krev/Rap1 相互作用陷获蛋白-1）突变存在于约 40%的常染色体显性遗传性脑动静脉畸形（CCM）中，这种疾病在人群中的发病率高达 0.5%。我们发现 KRIT1 通过拮抗 ICAP1（整合素细胞质相关蛋白-1）介导的“内-外”激活调节，作为β1 整合素激活的开关。我们展示了 KRIT1 与 ICAP1 的共晶结构和 ICAP1 与整合素β1 胞质尾的共晶结构，分辨率分别为 2.54 和 3.0Å（I/σI=2 时的分辨率分别为 2.75 和 3.0Å）。我们发现 KRIT1 通过双齿表面与 ICAP1 结合，KRIT1 直接与整合素β1 竞争与 ICAP1 结合，并且 KRIT1 使用该位点拮抗 ICAP1 调节的整合素激活。我们还发现 KRIT1 含有一个 N 端 Nudix 结构域，该结构域位于以前被指定为无结构的区域。因此，我们为整合素调节和 CCM 相关 KRIT1 功能提供了新的见解。
