Dataset Information

Autonomous conformational regulation of ?3 integrin and the conformation-dependent property of HPA-1a alloantibodies.

ABSTRACT: Integrin ?/? 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 ? subunit induce the ?/? 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 ?3 integrins, including ?IIb?3 and ?V?3, are the prototypes for understanding integrin structural regulation. The Leu33Pro polymorphism located at the ?3 PSI 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 ?IIb?3 from ?V?3 and affect their functions with unknown mechanisms. Here we designed a single-chain ?3 subunit that mimics a separation of ?/? heterodimer on inside-out activation. Our crystallographic and functional studies show that the single-chain ?3 integrin folds into a bent conformation in solution but spontaneously extends on the cell surface. This demonstrates that the ?3 subunit autonomously drives the membrane-dependent conformational rearrangement during integrin activation. Using the single-chain ?3 integrin, we identified the conformation-dependent property of anti-HPA-1a alloantibodies, which enables them to differently recognize the ?3 in the bent state vs. the extended state and in the complex with ?IIb vs. ?V This study provides deeper understandings of integrin conformational activation on the cell surface.

SUBMITTER: Thinn AMM

PROVIDER: S-EPMC6166792 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Publications

Autonomous conformational regulation of β<sub>3</sub> integrin and the conformation-dependent property of HPA-1a alloantibodies.

Thinn Aye Myat Myat AMM Wang Zhengli Z Zhou Dongwen D Zhao Yan Y Curtis Brian R BR Zhu Jieqing J

Proceedings of the National Academy of Sciences of the United States of America 20180912 39

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 whi ...[more]

PMID: 30209215

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Project description:The neuropeptide vasopressin (VP) and its three G protein-coupled receptors (V1aR, V1bR and V2R) are of high interest in a wide array of drug discovery programs. V1aR is of particular importance due to its cardiovascular functions and diverse roles in the central nervous system. The structure-activity relationships underpinning ligand-receptor interactions remain however largely unclear, hindering rational drug design. This is not least due to the high structural flexibility of VP in its free as well as receptor-bound states. In this work, we developed a novel approach to reveal features of conformational selectivity upon VP-V1aR complex formation. We employed virtual screening strategies to probe VP's conformational space for transiently adopted structures that favor binding to V1aR. To this end, we dissected the VP conformational space into three sub-ensembles, each containing distinct structural sets for VP's three-residue C-terminal tail. We validated the computational results with experimental nuclear magnetic resonance (NMR) data and docked each sub-ensemble to V1aR. We observed that the conformation of VP's three-residue tail significantly modulated the complex dissociation constants. Solvent-exposed and proline trans-configured VP tail conformations bound to the receptor with three-fold enhanced affinities compared to compacted or cis-configured conformations. The solvent-exposed and more flexible structures facilitated unique interaction patterns between VP and V1aR transmembrane helices 3, 4, and 6 which led to high binding energies. The presented "virtual conformational space screening" approach, integrated with NMR spectroscopy, thus enabled identification and characterization of a conformational selection-type complex formation mechanism that confers novel perspectives on targeting the VP-V1aR interactions at the level of the encounter complex - an aspect that opens novel research avenues for understanding the functionality of the evolutionary selected conformational properties of VP, as well as guidance for ligand design strategies to provide more potent and selective VP analogues.

Dataset Information

Autonomous conformational regulation of ?3 integrin and the conformation-dependent property of HPA-1a alloantibodies.

Publications

Autonomous conformational regulation of β<sub>3</sub> integrin and the conformation-dependent property of HPA-1a alloantibodies.

Similar Datasets

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