Autonomous conformational regulation of β3 integrin and the conformation-dependent property of HPA-1a alloantibodies.
Autonomous conformational regulation of β3 integrin and the conformation-dependent property of HPA-1a alloantibodies.
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β3 整合素的自主构象调节和 HPA-1a 同种抗体的构象依赖性。
DOI：
10.1073/pnas.1806205115
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发表时间：
2018
影响因子：
11.1
通讯作者：
Zhu,Jieqing
中科院分区：
文献类型：
--
作者：
Thinn,AyeMyatMyat;Wang,Zhengli;Zhou,Dongwen;Zhao,Yan;Curtis,BrianR;Zhu,Jieqing
整合素α/β异源二聚体在静息状态下采用紧凑的弯曲构象，并且在活化时经历大规模构象重排。在由内而外激活过程中，撞击β亚基胞质尾部的信号诱导跨膜和胞质结构域处的α/β分离，导致具有分离的腿部和开放的头部的胞外域的延伸构象，这是高亲和力配体结合所需的。在由内而外的激活过程中，整合素亚基驱动的构象重排仍然是个谜。β 3整合素（包括αIIbβ 3和αVβ3）是了解整合素结构调控的原型。位于β 3 PSI结构域的Leu 33 Pro多态性定义了人血小板特异性同种异体抗原（HPA）1a/B，其引起同种免疫应答，导致临床上重要的出血性疾病。一些但不是全部的抗HPA-1a同种抗体可以区分αIIbβ 3和αVβ 3，并以未知的机制影响它们的功能。在这里，我们设计了一个单链β 3亚基，它模拟了α/β异源二聚体在由内而外激活时的分离。我们的晶体学和功能研究表明，单链β 3整合素在溶液中折叠成弯曲构象，但在细胞表面自发延伸。这表明β 3亚基在整合素活化过程中自主驱动膜依赖性构象重排。利用单链β 3整合素，我们鉴定了抗HPA-1a同种抗体的构象依赖性，这使得它们能够不同地识别弯曲状态和伸展状态以及与αIIbvs复合物中的β 3。αV这项研究提供了更深入的了解整合素的构象激活细胞表面。
Integrin α/β heterodimer adopts a compact bent conformation in the resting state, and upon activation undergoes a large-scale conformational rearrangement. During the inside-out activation, signals impinging on the cytoplasmic tail of β subunit induce the α/β separation at the transmembrane and cytoplasmic domains, leading to the extended conformation of the ectodomain with the separated leg and the opening headpiece that is required for the high-affinity ligand binding. It remains enigmatic which integrin subunit drives the bent-to-extended conformational rearrangement in the inside-out activation. The β3integrins, including αIIbβ3and αVβ3, are the prototypes for understanding integrin structural regulation. The Leu33Pro polymorphism located at the β3PSI domain defines the human platelet-specific alloantigen (HPA) 1a/b, which provokes the alloimmune response leading to clinically important bleeding disorders. Some, but not all, anti–HPA-1a alloantibodies can distinguish the αIIbβ3from αVβ3and affect their functions with unknown mechanisms. Here we designed a single-chain β3subunit that mimics a separation of α/β heterodimer on inside-out activation. Our crystallographic and functional studies show that the single-chain β3integrin folds into a bent conformation in solution but spontaneously extends on the cell surface. This demonstrates that the β3subunit autonomously drives the membrane-dependent conformational rearrangement during integrin activation. Using the single-chain β3integrin, we identified the conformation-dependent property of anti–HPA-1a alloantibodies, which enables them to differently recognize the β3in the bent state vs. the extended state and in the complex with αIIbvs. αV. This study provides deeper understandings of integrin conformational activation on the cell surface.