Structural Basis for Small G Protein Effector Interaction of Ras-related Protein 1 (Rap1) and Adaptor Protein Krev Interaction Trapped 1 (KRIT1)
Structural Basis for Small G Protein Effector Interaction of Ras-related Protein 1 (Rap1) and Adaptor Protein Krev Interaction Trapped 1 (KRIT1)
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DOI：
10.1074/jbc.m112.361295
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发表时间：
2012-06-22
影响因子：
4.8
通讯作者：
Boggon, Titus J.
中科院分区：
文献类型：
--
作者：
Li, Xiaofeng;Zhang, Rong;Boggon, Titus J.
脑海绵状血管瘤 (CCM) 影响 0.1-0.5% 的人口，导致脉管系统渗漏和严重的神经缺陷。 KRIT1（Krev 相互作用捕获-1）突变与约 40% 的家族性 CCM 相关。 KRIT1 是 Ras 相关蛋白 1 (Rap1) GTPase 的效应子。 Rap1 将 KRIT1 从微管重新定位到细胞膜，以影响整合素激活，这对 CCM 病理学可能很重要。我们报道了与 Rap1 复合的 KRIT1 FERM 结构域的 1.95 埃共晶结构。 Rap1-KRIT1 相互作用涵盖了一个扩展的表面，包括 Rap1 Switch I 和 II 以及 KRIT1FERMF1 和 F2 叶。 Rap1 使用 GTPase-泛素样折叠相互作用结合 KRIT1-F1 叶，但通过新颖的相互作用结合 KRIT1-F2 叶。点突变证实了相互作用。揭示了 KRIT1-F2/F3 和 talin 之间的高度相似性。此外，还提出了 FERM 结构域作为 GTPase 效应器的机制。最后，每个叶的基于结构的对齐表明将 FERM 结构域分类为 ERM 样和 TMFK 样（talin-myosin-FAK-KRIT 样），并且 FERM 叶类似于结构域“模块”。
Cerebral cavernous malformations (CCMs) affect 0.1-0.5% of the population resulting in leaky vasculature and severe neurological defects. KRIT1 (Krev interaction trapped-1) mutations associate with similar to 40% of familial CCMs. KRIT1 is an effector of Ras-related protein 1 (Rap1) GTPase. Rap1 relocalizes KRIT1 from microtubules to cell membranes to impact integrin activation, potentially important for CCM pathology. We report the 1.95 angstrom co-crystal structure of KRIT1 FERM domain in complex with Rap1. Rap1-KRIT1 interaction encompasses an extended surface, including Rap1 Switch I and II and KRIT1FERMF1 and F2 lobes. Rap1 binds KRIT1-F1 lobe using a GTPase-ubiquitin-like fold interaction but binds KRIT1-F2 lobe by a novel interaction. Point mutagenesis confirms the interaction. High similarity between KRIT1-F2/F3 and talin is revealed. Additionally, the mechanism for FERM domains acting as GTPase effectors is suggested. Finally, structure-based alignment of each lobe suggests classification of FERM domains as ERM-like and TMFK-like (talin-myosin-FAK-KRIT-like) and that FERM lobes resemble domain "modules."