Mechanical switching and coupling between two dissociation pathways in a P-selectin adhesion bond
Mechanical switching and coupling between two dissociation pathways in a P-selectin adhesion bond
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DOI：
10.1073/pnas.0401870101
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发表时间：
2004-08-03
影响因子：
11.1
通讯作者：
Zhu, C
中科院分区：
文献类型：
--
作者：
Evans, E;Leung, A;Zhu, C
许多生物分子键表现出机械强度，其与力施加速率的对数成比例地增加。与上升力下键寿命的指数下降一致，这种动力学上有限的失效反映了沿着沿着一个单一的热力学途径的解离，该途径受到尖锐的自由能势垒的阻碍。使用灵敏的力探针测试白细胞粘附键P-选择素糖蛋白配体1（PSG-Li）-P-选择素，我们观察到力施加速率从300到30，000 pN/sec每增加10倍，键强度线性增加，这意味着失效的单一途径。然而，当负载低于300 pN/sec时，PSGL-1-P-选择素键的强度和寿命急剧下降，表明出乎意料地更快的解离和可能的第二失效途径。值得注意的是，如果首先通过力的“跳跃”加载到20-30 pN，则当经受慢至30 pN/sec的力斜坡时，键变强，并且在所有力速率下表现出相同的单途径动力学。以这种方式应用，一个新的“跳跃/斜坡”模式的力谱显示，PSGL-1-P-选择素键的行为作为一个机械化学开关，其中力的历史选择两个解离途径之间具有显着不同的属性。此外，PSGL-1被其19-aa N末端的变体和关键的四糖唾液酸基刘易斯（x）取代，在失效动力学中产生了显著的变化，表明了两种途径的结构基础。双通道开关似乎提供了一种机制，最近观察到的“捕捉债券”的反应与PSGL-1-P-选择素债券受到小恒定的力量。
Many biomolecular bonds exhibit a mechanical strength that increases in proportion to the logarithm of the rate of force application. Consistent with exponential decrease in bond lifetime under rising force, this kinetically limited failure reflects dissociation along a single thermodynamic pathway impeded by a sharp free energy barrier. Using a sensitive force probe to test the leukocyte adhesion bond P-selectin glycoprotein ligand 1 (PSG-Li)-P-selectin, we observed a linear increase of bond strength with each 10-fold increase in the rate of force application from 300 to 30,000 pN/sec, implying a single pathway for failure. However, the strength and lifetime of PSGL-1-P-selectin bonds dropped anomalously when loaded below 300 pN/sec, demonstrating unexpectedly faster dissociation and a possible second pathway for failure. Remarkably, if first loaded by a "jump" in force to 20-30 pN, the bonds became strong when subjected to a force ramp as slow as 30 pN/sec and exhibited the same single-pathway kinetics under all force rates. Applied in this way, a new "jump/ramp" mode of force spectroscopy was used to show that the PSGL-1-P-selectin bond behaves as a mechanochemical switch where force history selects between two dissociation pathways with markedly different properties. Furthermore, replacing PSGL-1 by variants of its 19-aa N terminus and by the crucial tetrasaccharide sialyl Lewis(x) produces dramatic changes in the failure kinetics, suggesting a structural basis for the two pathways. The two-pathway switch seems to provide a mechanism for the "catch bond" response observed recently with PSGL-1-P-selectin bonds subjected to small-constant forces.