Intersubunit signal transmission in integrins by a receptor-like interaction with a pull spring.
Intersubunit signal transmission in integrins by a receptor-like interaction with a pull spring.
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DOI：
10.1073/pnas.0307340101
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发表时间：
2004-03
影响因子：
11.1
通讯作者：
Wei Yang;M. Shimaoka;A. Salas;J. Takagi;T. Springer
中科院分区：
文献类型：
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作者：
Wei Yang;M. Shimaoka;A. Salas;J. Takagi;T. Springer
一些多结构域蛋白的功能受结构域间通讯的调控。我们使用第二位点抑制因子半胱氨酸突变来验证整合素β亚基中插入(I)样结构域如何通过整合素α亚基中的相邻I结构域调节配体结合的假设[Huth， J. R., Olejniczak， E. T., Mendoza， R., Liang， H., Harris， E. a ., et . (2000) Proc. Natl。学会科学。美国97,5231-5236；和Alonso， J. L, Essafi， M., Xiong， J. P., Stehle， T.和Arnaout， M. A. (2002) [j]。生物工程学报，2012,32(4):444 - 444。假设是β I类金属离子依赖粘附位点（MIDAS）与α I结构域后的连接体中的内在配体（glu310）之间的相互作用施加了激活α I结构域的拉力。α (L)连接体残基Glu-310或β (2) MIDAS残基Ala-210或tir -115对半胱氨酸的单个突变会消除I结构域的激活，而α (L)-E310C与β (2)-A210C或β (2)-Y115C的双重突变会形成二硫键，从而组成性地激活配体结合。二硫化物结合突变体对与α I结构域界面附近的β I样结构域结合并抑制这些结构域之间的通信的小分子拮抗剂具有抗性，但对结合在α 7-螺旋结构域下方的小分子拮抗剂和某些变构拮抗抗体仍然敏感。因此，alpha 7-helix和它的连接件被更好地建模为拉簧而不是钟绳。结果表明，α (L)残基Glu-310在所有含I结构域的整合素中普遍保守，作为β - I-like结构域的内在配体，当整合素被激活时，β - I-like MIDAS与Glu-310结合，拉弹簧，从而激活α - I结构域。
The function of some multidomain proteins is regulated by interdomain communication. We use second-site suppressor cysteine mutations to test a hypothesis on how the inserted (I)-like domain in the integrin beta-subunit regulates ligand binding by the neighboring I domain in the integrin alpha-subunit [Huth, J. R., Olejniczak, E. T., Mendoza, R., Liang, H., Harris, E. A., et al. (2000) Proc. Natl. Acad. Sci. USA 97, 5231-5236; and Alonso, J. L., Essafi, M., Xiong, J. P., Stehle, T. & Arnaout, M. A. (2002) Curr. Biol. 12, R340-R342]. The hypothesis is that an interaction between the beta I-like metal ion-dependent adhesion site (MIDAS) and an intrinsic ligand in the linker following the alpha I domain, Glu-310, exerts a pull that activates the alpha I domain. Individual mutation of alpha(L) linker residue Glu-310 or beta(2) MIDAS residues Ala-210 or Tyr-115 to cysteine abolishes I domain activation, whereas the double mutation of alpha(L)-E310C with either beta(2)-A210C or beta(2)-Y115C forms a disulfide bond that constitutively activates ligand binding. The disulfide-bonded mutant is resistant to small molecule antagonists that bind to the beta I-like domain near its interface with the alpha I domain and inhibit communication between these domains but remains susceptible to small molecule antagonists that bind underneath the I domain alpha 7-helix and certain allosteric antagonistic antibodies. Thus, the alpha 7-helix and its linker are better modeled as a pull spring than a bell rope. The results suggest that alpha(L) residue Glu-310, which is universally conserved in all I domain-containing integrins, functions as an intrinsic ligand for the beta I-like domain, and that when integrins are activated, the beta I-like MIDAS binds to Glu-310, pulls the spring, and thereby activates the alpha I domain.