Key Laboratory of Microgravity, Institute of Mechanics, Chinese Academy of Sciences, Beijing, P. R. China.
PLoS One. 2011;6(8):e24188. doi: 10.1371/journal.pone.0024188. Epub 2011 Aug 31.
β₂ integrin of lymphocyte function-associated antigen-1 (LFA-1) or macrophage-1 antigen (Mac-1) binds to their common ligand of intercellular adhesion molecule-1 (ICAM-1) and mediates leukocyte-endothelial cell (EC) adhesions in inflammation cascade. Although the two integrins are known to have distinct functions, the corresponding micro-structural bases remain unclear. Here (steered-)molecular dynamics simulations were employed to elucidate the conformational stability of α subunit I domains of LFA-1 and Mac-1 in different affinity states and relevant I domain-ICAM-1 interaction features. Compared with low affinity (LA) Mac-1, the LA LFA-1 I domain was unstable in the presence or absence of ICAM-1 ligand, stemming from diverse orientations of its α₇-helix with different motifs of zipper-like hydrophobic junction between α₁- and α₇-helices. Meanwhile, spontaneous transition of LFA-1 I domain from LA state to intermediate affinity (IA) state was first visualized. All the LA, IA, and high affinity (HA) states of LFA-1 I domain and HA Mac-1 I domain were able to bind to ICAM-1 ligand effectively, while LA Mac-1 I domain was unfavorable for binding ligand presumably due to the specific orientation of S144 side-chain that capped the MIDAS ion. These results furthered our understanding in correlating the structural bases with their functions of LFA-1 and Mac-1 integrins from the viewpoint of I domain conformational stability and of the characteristics of I domain-ICAM-1 interactions.
淋巴细胞功能相关抗原-1（LFA-1）或巨噬细胞-1 抗原（Mac-1）的β₂整合素与细胞间黏附分子-1（ICAM-1）的共同配体结合，并在炎症级联中介导白细胞-内皮细胞（EC）黏附。尽管这两种整合素具有不同的功能，但相应的微观结构基础仍不清楚。在这里，采用（导向）分子动力学模拟来阐明 LFA-1 和 Mac-1 的α亚基 I 结构域在不同亲和力状态下的构象稳定性，以及相关的 I 结构域-ICAM-1 相互作用特征。与低亲和力（LA）Mac-1 相比，LA LFA-1 I 结构域在存在或不存在 ICAM-1 配体的情况下不稳定，这源于其α₇-螺旋的不同取向，以及α₁-和α₇-螺旋之间拉链状疏水区之间的不同模体。同时，首次可视化了 LFA-1 I 结构域从 LA 状态到中间亲和力（IA）状态的自发转变。LFA-1 I 结构域的所有 LA、IA 和高亲和力（HA）状态以及 HA Mac-1 I 结构域都能够有效地与 ICAM-1 配体结合，而 LA Mac-1 I 结构域不利于结合配体，可能是由于 S144 侧链的特定取向阻碍了 MIDAS 离子。这些结果从 I 结构域构象稳定性和 I 结构域-ICAM-1 相互作用的特征的角度，进一步了解了 LFA-1 和 Mac-1 整合素的结构基础与其功能之间的关系。
