title: Conformational stability analyses of alpha subunit I domain of LFA-1 and Mac-1.
abstract: 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.
authors: Key Laboratory of Microgravity, Institute of Mechanics, Chinese Academy of Sciences, Beijing, P. R. China.
authors: Debin
authors: D
authors: Mao
authors: Shouqin
authors: S
authors: Lü
authors: Ning
authors: N
authors: Li
authors: Yan
authors: Y
authors: Zhang
authors: Mian
authors: M
authors: Long
mesh_terms: D000495:Allosteric Site; D057927:Hydrophobic and Hydrophilic Interactions; D018799:Intercellular Adhesion Molecule-1 / Q000737:chemistry / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000737:chemistry*; D016177:Macrophage-1 Antigen / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D055550:Protein Stability; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: D016169:Lymphocyte Function-Associated Antigen-1; D016177:Macrophage-1 Antigen; D018799:Intercellular Adhesion Molecule-1