Integrins are a structurally elaborate family of adhesion molecules that transmit signals bidirectionally across the plasma membrane by undergoing large-scale structural rearrangements. By regulating cell-cell and cell-matrix contacts, integrins participate in a wide-range of biological interactions including development, tissue repair, angiogenesis, inflammation and hemostasis. From a therapeutic standpoint, integrins are probably the most important class of cell adhesion receptors. Structural investigations on integrin-ligand interactions reveal remarkable features in molecular detail. These details include the atomic basis for divalent cation-dependent ligand binding and how conformational signals are propagated long distances from one domain to another between the cytoplasm and the extracellular ligand binding site that regulate affinity for ligand, and conversely, cytosolic signaling pathways.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.
"All these events strongly depend on physical linking of fibrinogen, integrin αIIbβ3 and cytoplasmic actin filaments into a stable complex which serves for transmission of contractile force from platelet to platelet within aggregates and from platelet to the thrombogenic surface . Despite numerous elegant studies showing the molecular mechanisms of αIIbβ3 conformational switches, interaction with its ligands, signaling molecules and membrane skeleton proteins     , regulation of the fibrinogen–αIIbβ3–actin cytoskeleton complex formation at the cellular level has not been fully characterized. It was shown that upon activation platelet cytoskeleton undergoes significant rearrangement including severing of existing actin filaments and assembly of new Thrombosis Research xxx (2014) xxx–xxx Abbreviations: ACD, acid-citrate-dextrose; ADP, adenosine diphosphate; ASA, acetylsalicylic acid; FFD, fibrinogen fragment D; LIBS6, ligand-induced binding site 6; mAb, monoclonal antibody; PAGE, polyacrylamide gel electrophoresis; PBS, phosphate-buffered saline; PPP, platelet-poor plasma; PRP, platelet-rich plasma; SD, standard deviation; SDS, sodium dodecyl sulfate; TBS, Tris-buffered saline; TBS-T, TBS containing 0.1% (v/v) Tween 20; TRAP, thrombin receptor-activating peptide; TXA 2 , thromboxane A 2 . "
"Integrins are noncovalently associated αβ heterodimeric cell surface receptors that mediate cell-cell and cell-extracellular matrix adhesions, signaling bidirectionally across the plasma membrane. Integrins play important roles in development, immune cell trafficking and responses, and homeostasis , , . One of the major leukocyte integrins is the lymphocyte function-associated antigen (LFA)-1, which provides the interactions necessary for immunological synapse formation and adhesion to endothelial cells . "
[Show abstract][Hide abstract] ABSTRACT: Intermolecular contacts between integrin LFA-1 (α(L)β(2)) and ICAM-1 derive solely from the integrin α(L) I domain and the first domain (D1) of ICAM-1. This study presents a crystal structure of the engineered complex of the α(L) I domain and ICAM-1 D1. Previously, we engineered the I domain for high affinity by point mutations that were identified by a directed evolution approach. In order to examine α(L) I domain allostery between the C-terminal α7-helix (allosteric site) and the metal-ion dependent adhesion site (active site), we have chosen a high affinity variant without mutations directly influencing either the position of the α7-helix or the active sites. In our crystal, the α(L) I domain was found to have a high affinity conformation to D1 with its α7-helix displaced downward away from the binding interface, recapitulating a current understanding of the allostery in the I domain and its linkage to neighboring domains of integrins in signaling. To enable soluble D1 of ICAM-1 to fold on its own, we also engineered D1 to be functional by mutations, which were found to be those that would convert hydrogen bond networks in the solvent-excluded core into vdW contacts. The backbone structure of the β-sandwich fold and the epitope for I domain binding of the engineered D1 were essentially identical to those of wild-type D1. Most deviations in engineered D1 were found in the loops at the N-terminal region that interacts with human rhinovirus (HRV). Structural deviation found in engineered D1 was overall in agreement with the function of engineered D1 observed previously, i.e., full capacity binding to α(L) I domain but reduced interaction with HRV.
"The signal transduction occurs mainly through integrins. Integrins interact with ECM and cytoskeleton, in co-operation with other receptors such as growth factor receptors (Yamada et al., 1980; ffrench-Constant and Colognato, 2004; Humphries et al., 2004; Springer and Wang, 2004). Because heparin binds to fibronectin and several other ECM molecules (Yamada et al., 1980; Barkalow and Schwarzbauer, 1991), integrin participation in the up-regulation of HSPG was investigated. "