「Structural biology of the small G protein Rho by X-ray analyses of the molecular complexes」

ERM蛋白通过连接肌动蛋白细丝和黏附分子，如CD44、CD43和ICAM，免疫球蛋白家族黏附分子，在膜相关细胞骨架的形成中起关键作用。ERM蛋白还与钠和氢离子交换调节因子(NHERF)结合，NHERF与离子通道NHE相互作用，调节通道的活性。ERM蛋白的这些结合活性是通过与Rho信号通路下游的磷脂酰肌醇4，5-二磷酸(PP2)结合而启动的。有趣的是，ERM蛋白的N端保守结构域PERM(4.1和ERM)结构域介导了与IPS、ICAM-2和RhoGDL的多重相互作用。我们测定了与这些结合伙伴形成的RadixPerm结构域复合体的晶体结构，并讨论了ERM蛋白完成多分子识别的分子机制。基于络合物的三维结构，我们已经确定了可能的ERM结合伙伴，包括Li-CAM。我们还确定了作为NFn基因产物的Merlin的perm结构域，并阐明了从NFn患者中获得的几个突变的结构和功能效应。最后，我们成功地确定了Rho-Kinase的Rho结合域的晶体结构，并阐明了该结合域与蛋白激酶N的相似性和差异性。

ERM (ezrin/radixin/moesin) proteins play a key role in the formation of the membrane-associated cytoskeleton by linking actin filaments and adhesion molecules such as CD44, CD43 and ICAMs, immunoglobulin-family adhesion molecules. ERM proteins also bind sodium and hydrogen ion exchanger regulatory factors (NHERFs), which interact with the ion channel NHE to modify the channel activity. These binding activities of ERM proteins are initiated by binding to phosphatidylinositol 4,5-bisphosphate (PP2) in the downstream of the Rho signaling pathway. Interestingly, the N-terminal conserved domain of ERM proteins, the PERM (4. 1 and ERM) domain, mediates the multiple interactions with IPS, ICAM-2, and RhoGDL We have determined the crystal structures of the radixin PERM domain complexefl with these binding partners and discussed the molecular mechanisms by which ERM proteins accomplish the multiple molecular recognition. Based on the three-dimensional structures of the complexes, we have addressed possible ERM-binding partners including LI-CAM. We have also determined the PERM domain of merlin, which is a gene product of NF n and elucidated the structural and functional effects of several mutations obtained from NF n patients. Finally, we have succeeded to determine the crystal structure of the Rho-binding domain of Rho-kinase and clarified the similarity and dissimilarity of the domain compared with that of protein kinase N.