Matsubara Mamoru, Nakatsu Toru, Kato Hiroaki, Taniguchi Hisaaki
Membrane Dynamics Project, Harima Institute at SPring-8, RIKEN, Sayo, Hyogo, Japan.
EMBO J. 2004 Feb 25;23(4):712-8. doi: 10.1038/sj.emboj.7600093. Epub 2004 Feb 12.
A variety of viral and signal transduction proteins are known to be myristoylated. Although the role of myristoylation in protein-lipid interaction is well established, the involvement of myristoylation in protein-protein interactions is less well understood. CAP-23/NAP-22 is a brain-specific protein kinase C substrate protein that is involved in axon regeneration. Although the protein lacks any canonical calmodulin (CaM)-binding domain, it binds CaM with high affinity. The binding of CAP-23/NAP-22 to CaM is myristoylation dependent and the N-terminal myristoyl group is directly involved in the protein-protein interaction. Here we show the crystal structure of Ca2+-CaM bound to a myristoylated peptide corresponding to the N-terminal domain of CAP-23/NAP-22. The myristoyl moiety of the peptide goes through a hydrophobic tunnel created by the hydrophobic pockets in the N- and C-terminal domains of CaM. In addition to the myristoyl group, several amino-acid residues in the peptide are important for CaM binding. This is a novel mode of binding and is very different from the mechanism of binding in other CaM-target complexes.
已知多种病毒蛋白和信号转导蛋白会被豆蔻酰化。虽然豆蔻酰化在蛋白质 - 脂质相互作用中的作用已得到充分证实，但豆蔻酰化在蛋白质 - 蛋白质相互作用中的参与情况却了解较少。CAP - 23/NAP - 22是一种大脑特异性蛋白激酶C底物蛋白，参与轴突再生。尽管该蛋白缺乏任何典型的钙调蛋白（CaM）结合结构域，但它能以高亲和力结合CaM。CAP - 23/NAP - 22与CaM的结合依赖于豆蔻酰化，且N端的豆蔻酰基团直接参与蛋白质 - 蛋白质相互作用。在此，我们展示了与对应于CAP - 23/NAP - 22 N端结构域的豆蔻酰化肽段结合的Ca²⁺ - CaM的晶体结构。该肽段的豆蔻酰部分穿过由CaM的N端和C端结构域中的疏水口袋形成的疏水通道。除了豆蔻酰基团外，肽段中的几个氨基酸残基对CaM结合也很重要。这是一种新颖的结合模式，与其他CaM - 靶标复合物的结合机制非常不同。
