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首页> 外文期刊>Journal of Molecular Biology >A transmembrane polar interaction is involved in the functional regulation of integrin alpha L beta 2.
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A transmembrane polar interaction is involved in the functional regulation of integrin alpha L beta 2.

机译：跨膜极性相互作用参与整联蛋白αL beta 2的功能调节。

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Integrins are heterodimeric transmembrane (TM) receptors formed by noncovalent associations of alpha and beta subunits. Each subunit contains a single alpha-helical TM domain. Inside-out activation of an integrin involves the separation of its cytoplasmic tails, leading to disruption of alphabeta TM packing. The leukocyte integrin alpha L beta 2 is required for leukocyte adhesion, migration, proliferation, cytotoxic function, and antigen presentation. In this study, we show by mutagenesis experiments that the packing of alpha L beta 2 TMs is consistent with that of the integrin alpha IIb beta 3 TMs. However, molecular dynamics simulations of alpha L beta 2 TMs in lipids predicted a polar interaction involving the side chains of alpha L Ser1071 and beta2 Thr686 in the outer-membrane association clasp (OMC). This is supported by carbonyl vibrational shifts observed in isotope-labeled alpha L beta 2 TM peptides that were incorporated into lipid bilayers. Molecular dynamics studies simulating the separation of alpha L beta 2 tails showed the presence of polar interaction during the initial perturbation of the inner-membrane association clasp. When the TMs underwent further separation, the polar interaction was disrupted. OMC polar interaction is important in regulating the functions of beta2 integrins because mutations that disrupt the OMC polar interaction generated constitutively activated alpha L beta 2, alpha M beta 2, and alpha X beta 2 in 293T transfectants. We also show that the expression of mutant beta2 Thr686Gly in beta2-deficient T cells rescued cell adhesion to intercellular adhesion molecule 1, but the cells showed overt elongated morphologies in response to chemokine stromal-cell-derived factor 1 alpha treatment as compared to wild-type beta2-expressing cells. These two TM polar residues are totally conserved in other members of the beta2 integrins in humans and across different species. Our results provide an example of the stabilizing effect of polar interactions within the low dielectric environment of the membrane interior and demonstrate its importance in the regulation of alpha L beta 2 function.
机译：整联蛋白是由α和β亚基的非共价结合形成的异二聚跨膜（TM）受体。每个亚基均包含单个α-螺旋TM结构域。整联蛋白的由内而外的激活涉及其胞质尾部的分离，从而导致字母TM包装的破坏。白细胞整合素αLβ2是白细胞粘附，迁移，增殖，细胞毒性功能和抗原呈递所必需的。在这项研究中，我们通过诱变实验表明，αLβ2 TM的包装与整联蛋白αIIbβ3 TM的包装一致。然而，脂质中的αLβ2 TM的分子动力学模拟预测极性相互作用涉及外膜缔合扣（OMC）中的αL Ser1071和β2Thr686的侧链。在掺入脂质双层的同位素标记的αLβ2 TM肽中观察到的羰基振动位移支持了这一点。分子动力学研究模拟了αLβ2尾巴的分离，表明内膜缔合扣的初始扰动期间存在极性相互作用。当TM进行进一步分离时，极性相互作用被破坏。 OMC极性相互作用在调节beta2整联蛋白的功能中很重要，因为破坏OMC极性相互作用的突变在293T转染子中产生了组成型激活的αL beta 2，αM beta 2和alpha X beta 2。我们还显示，β2缺陷型T细胞中突变体beta2 Thr686Gly的表达挽救了细胞对细胞间粘附分子1的粘附，但与野生型相比，细胞显示了对趋化因子基质细胞衍生因子1α治疗的明显延长的形态。 β2型表达细胞。这两个TM极性残基在人类以及不同物种的β2整合素的其他成员中完全保守。我们的结果提供了一个示例，说明了在膜内部低介电环境中极性相互作用的稳定作用，并证明了其在调节αLβ2功能中的重要性。

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