Local conformational flexibility provides a basis for facile polymer formation in human neuroserpin.
Local conformational flexibility provides a basis for facile polymer formation in human neuroserpin.
复制标题
局部构象灵活性为人神经丝氨酸蛋白酶抑制剂中容易形成聚合物提供了基础。
DOI：
10.1016/j.bpj.2011.08.037
复制
发表时间：
2011
影响因子：
3.4
通讯作者：
Wintrode,PatrickL
中科院分区：
文献类型：
--
作者：
Sarkar,Anindya;Zhou,Crystal;Meklemburg,Robert;Wintrode,PatrickL
神经丝氨酸蛋白酶抑制剂是神经元生长和可塑性的调节剂。与丝氨酸蛋白酶抑制剂家族的其他成员一样，神经丝氨酸蛋白酶抑制剂经历了大的构象变化作为其功能的一部分。与其他丝氨酸蛋白酶抑制剂如α1-抗胰蛋白酶不同，野生型神经丝氨酸蛋白酶抑制剂在接近生理的条件下会自发地转变为潜伏状态。为了探索这种构象不稳定性的起源，我们对人类神经丝氨酸蛋白酶进行了氢交换测量和分子动力学模拟。氢交换表明，与α1-抗胰蛋白酶相比，neuroserpin在缺口区域和β-链1C中具有更大的柔性。分子动力学模拟表明，β链3和5A的顶端之间的距离平均为4.6 μ m，但在neuroserpin中变得高达7.5 μ m，而在α1-抗胰蛋白酶中保持稳定在3.5 μ m。进一步的模拟表明，稳定的S340 A突变抑制了神经丝氨酸蛋白酶抑制剂的这些波动。从模拟计算的第一主成分显示，在神经丝氨酸蛋白酶抑制剂中，螺旋F远离β-折叠A的表面移动，而在α1-抗胰蛋白酶中没有明显的这种移动。相对于α1-抗胰蛋白酶，神经丝氨酸蛋白酶抑制剂中这些区域的增加的移动性为神经丝氨酸蛋白酶抑制剂增加形成聚合物和/或潜伏状态的趋势提供了基础。
Neuroserpin is a regulator of neuronal growth and plasticity. Like other members of the serpin family, neuroserpin undergoes a large conformational change as part of its function. Unlike other serpins such asα1-antitrypsin, wild-type neuroserpin will polymerize under near-physiological conditions, and will spontaneously transition to the latent state. To probe the origins of this conformational lability, we have performed hydrogen exchange measurements and molecular-dynamics simulations on human neuroserpin. Hydrogen exchange indicates that neuroserpin has greater flexibility in the breach region and inβ-strand 1C compared withα1-antitrypsin. Molecular-dynamics simulations show that the distance between the top ofβ-strands 3 and 5A averages 4.6 Å but becomes as large as 7.5 Å in neuroserpin while it remains stable at ∼3.5 Å inα1-antitrypsin. Further simulations show that the stabilizing S340A mutation suppresses these fluctuations in neuroserpin. The first principal component calculated from the simulations shows a movement of helix F away from the face ofβ-sheet A in neuroserpin while no such movement is evident inα1-antitrypsin. The increased mobility of these regions in neuroserpin relative toα1-antitrypsin provides a basis for neuroserpin's increased tendency toward the formation of polymers and/or the latent state.