Global conformational rearrangements in integrin extracellular domains in outside-in and inside-out signaling
Global conformational rearrangements in integrin extracellular domains in outside-in and inside-out signaling
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DOI：
10.1016/s0092-8674(02)00935-2
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发表时间：
2002-09-06
期刊：
影响因子：
64.5
通讯作者：
Springer, TA
中科院分区：
文献类型：
--
作者：
Takagi, J;Petre, BM;Springer, TA
配体结合如何改变外向内信号中整合素的构象，以及内向外信号如何改变整合素与配体的亲和力，一直是个谜。我们通过电子显微镜、物理化学测量、二硫化物的突变引入以及与αVbeta3和alphaIIbbeta3整合素的配体结合来解决这一问题。我们发现，高度弯曲的整合素构象是生理的，对生物配体的亲和力很低。添加高亲和力配体模拟肽或Mn2+导致对延伸结构的开关叶片状开口。杂化结构域与类I结构域交界处的向外摆动显示了与配体结合有关的头盔内的构象变化。α和β亚基之间C-末端环的断裂增强了Mn2+诱导的去弯曲和配体结合。
How ligand binding alters integrin conformation in outside-in signaling, and how inside-out signals alter integrin affinity for ligand, have been mysterious. We address this with electron microscopy, physicochemical measurements, mutational introduction of disulfides, and ligand binding to alphaVbeta3 and alphaIIbbeta3 integrins. We show that a highly bent integrin conformation is physiological and has low affinity for biological ligands. Addition of a high affinity ligand mimetic peptide or Mn2+ results in a switch blade-like opening to an extended structure. An outward swing of the hybrid domain at its junction with the I-like domain shows conformational change within the headpiece that is linked to ligand binding. Breakage of a C-terminal clasp between the alpha and beta subunits enhances Mn2+ induced unbending and ligand binding.