Hanein Dorit, Volkmann Niels
Bioinformatics and Structural Biology Program, Sanford-Burnham-Prebys Medical Discovery Institute, San Diego, CA, USA.
Subcell Biochem. 2018;87:353-363. doi: 10.1007/978-981-10-7757-9_12.
Integrins are bidirectional transmembrane receptors that play central roles in hemostasis and arterial thrombosis. They have been subject to structural studies for many years, in particular using X-ray crystallography, nuclear magnetic resonance spectroscopy, and two-dimensional negative stain electron microscopy. Despite considerable progress, a full consensus on the molecular mechanism of integrin activation is still lacking. Three-dimensional reconstructions of full-length human platelet integrin αβ in lipid-bilayer nanodiscs obtained by electron cryo-microscopy and single-particle reconstruction have shed new light on the activation process. These studies show that integrin αβ exists in a continuous conformational equilibrium ranging from a compact nodular conformation similar to that obtained in crystal structures to a fully extended state with the leg domains separated. This equilibrium is shifted towards the extended conformation when extracellular ligands, cytosolic activators and lipid-bilayer nanodiscs are added. Addition of cytosolic activators and extracellular ligands in the absense of nanodiscs produces significantly less dramatic shifts, emphasizing the importance of the membrane bilayer in the activation process.
整合素是双向跨膜受体，在止血和动脉血栓形成中起核心作用。多年来，人们一直对其进行结构研究，特别是使用X射线晶体学、核磁共振光谱和二维负染电子显微镜。尽管取得了相当大的进展，但对于整合素激活的分子机制仍未达成完全共识。通过电子冷冻显微镜和单颗粒重建获得的脂质双层纳米盘中全长人血小板整合素αβ的三维重建为激活过程提供了新的线索。这些研究表明，整合素αβ存在于一个连续的构象平衡中，范围从类似于晶体结构中获得的紧密结节构象到腿部结构域分离的完全伸展状态。当添加细胞外配体、胞质激活剂和脂质双层纳米盘时，这种平衡向伸展构象移动。在没有纳米盘的情况下添加胞质激活剂和细胞外配体产生的变化要小得多，这强调了膜双层在激活过程中的重要性。
