Importance of force linkage in mechanochemistry of adhesion receptors
Importance of force linkage in mechanochemistry of adhesion receptors
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DOI：
10.1021/bi061566o
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发表时间：
2006-12-19
期刊：
影响因子：
2.9
通讯作者：
Springer, Timothy A.
中科院分区：
文献类型：
--
作者：
Astrof, Nathan S.;Salas, Azucena;Springer, Timothy A.
整合素α（L）β（2）[淋巴细胞功能相关抗原-1（LFA-1）]的α亚基插入（I）结构域与细胞间粘附分子-1（ICAM-1）结合。α I结构域的C-和N-末端在“下”面上彼此靠近，与“上”面上的金属离子依赖性粘附位点（MIDAS）相对。在转化为开放的α I结构域构象时，α 7埃向下，C末端螺旋α 7的轴向位移与MIDAS重排为其高亲和力构象发生变构关系。在这里，我们测试的假设，当施加的力是适当的构象变化，构象变化可以稳定的粘合剂相互作用，抵抗施加的力。整合素α I结构域分别使用I型或II型跨膜结构域通过其C-或N-末端锚定至细胞表面。C-末端而不是N-末端锚定有力地支持细胞在剪切流中在ICAM-1基质上滚动。相比之下，当α（L）I结构域突变稳定在开放构象与二硫键，它介导的I型和II型膜锚的牢固粘附相当的水平。为了排除作为差异粘附来源的其他效应，使用通过N-或C-末端缀合至聚苯乙烯微球的α I结构域复制这些结果。我们的研究结果表明，一个机械反馈系统，用于调节粘合剂粘结强度。综述了整合素α和β亚基I结构域和选择素在高亲和力和低亲和力构象中的晶体结构，证明了一种常见的机械化学设计，其中生物学施加的张力稳定了更延伸的高亲和力构象。
The alpha subunit-inserted ( I) domain of integrin alpha(L)beta(2) [ lymphocyte function- associated antigen-1 ( LFA-1)] binds to intercellular adhesion molecule-1 ( ICAM-1). The C- and N-termini of the alpha I domain are near one another on the "lower" face, opposite the metal ion-dependent adhesion site ( MIDAS) on the "upper face". In conversion to the open alpha I domain conformation, alpha 7 angstrom downward, axial displacement of C- terminal helix alpha 7 is allosterically linked to rearrangement of the MIDAS into its high-affinity conformation. Here, we test the hypothesis that when an applied force is appropriately linked to conformational change, the conformational change can stabilize adhesive interactions that resist the applied force. Integrin alpha I domains were anchored to the cell surface through their C- or N-termini using type I or II transmembrane domains, respectively. C- terminal but not N-terminal anchorage robustly supported cell rolling on ICAM-1 substrates in shear flow. In contrast, when the alpha(L) I domain was mutationally stabilized in the open conformation with a disulfide bond, it mediated comparable levels of firm adhesion with type I and type II membrane anchors. To exclude other effects as the source of differential adhesion, these results were replicated using alpha I domains conjugated through the N- or C- terminus to polystyrene microspheres. Our results demonstrate a mechanical feedback system for regulating the strength of an adhesive bond. A review of crystal structures of integrin alpha and beta subunit I domains and selectins in high- and low-affinity conformations demonstrates a common mechanochemical design in which biologically applied tensile force stabilizes the more extended, high- affinity conformation.