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Identification of the binding surface on Cdc42Hs for p21-activated kinase

机译：鉴定Cdc42Hs上p21活化激酶的结合表面

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The Ras superfamily of GTP-binding proteins is involved in a number of cellular signaling events including, but not limited to, tumorigenesis, intracellular trafficking, and cytoskeletal organization. The Rho subfamily, of which Cdc42Hs is a member, is involved in cell morphogenesis through a GTPase cascade which regulates cytoskeletal changes. Cdc42Hs has been shown to stimulate DNA synthesis as well as to initiate a protein kinase cascade that begins with the activation of the p21-activated serine/ threonine kinases (PAKs). We have determined previously the solution structure of Cdc42Hs [Feltham et al. (1997) Biochemistry 36, 8755-8766] using NMR spectroscopy. A minimal-binding domain of 46 amino acids of PAK was identified (PBD46), which binds Cdc42Hs with a K-D of approximately 20 nM and inhibits GTP hydrolysis. The binding interface was mapped by producing a fully deuterated sample of N-15-Cdc42Hs bound to PBD46. A H-1,N-15-NOESY-HSQC spectrum demonstrated that the binding surface on Cdc42Hs consists of the second beta-strand (beta 2) and a portion of the loop between the first alpha-helix (alpha 1) and beta 2 (switch I). A complex of PBD46 bound to N-15-Cdc42Hs.GMPPCP exhibited extensive chemical shift changes in the H-1,N-15-HSQC spectrum. Thus, PBD46 likely produces structural changes in Cdc42Hs which are not limited to the binding interface, consistent with its effects on GTP hydrolysis. These results suggest that the kinase-binding domain on Cdc42Hs is similar to, but more extensive than, the c-Raf-binding domain on the Ras antagonist, Rap1 [Nassar et al. (1995) Nature 375, 554-560)]. [References: 52]
机译：GTP结合蛋白的Ras超家族参与许多细胞信号转导事件，包括但不限于肿瘤发生，细胞内运输和细胞骨架组织。 Cdc42Hs是其成员的Rho亚家族，通过调节细胞骨架变化的GTPase级联参与细胞形态发生。已显示Cdc42Hs刺激DNA合成并启动蛋白激酶级联反应，该反应始于p21激活的丝氨酸/苏氨酸激酶（PAKs）的激活。我们先前已经确定了Cdc42Hs的溶液结构[Feltham等。 （1997）Biochemistry 36，8755-8766]使用NMR光谱。鉴定出PAK的46个氨基酸的最小结合域（PBD46），该结合域以约20 nM的K-D结合Cdc42Hs，并抑制GTP水解。通过产生与PBD46结合的N-15-Cdc42Hs的完全氘代样品来绘制结合界面。 H-1，N-15-NOESY-HSQC光谱表明Cdc42Hs的结合表面由第二个β链（beta 2）和第一个alpha螺旋（alpha 1）和beta 2之间的一部分环组成（开关I）。与N-15-Cdc42Hs.GMPPCP结合的PBD46复合物在H-1，N-15-HSQC光谱中表现出广泛的化学位移变化。因此，PBD46可能会在Cdc42Hs中产生结构变化，这种变化不限于结合界面，与其对GTP水解的影响一致。这些结果表明，Cdc42Hs上的激酶结合结构域与Ras拮抗剂Rap1上的c-Raf结合结构域相似，但比其更广泛[Nassar等人。 （1995）Nature 375，554-560）]。 [参考：52]

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