The mechanism of shared but distinct CSF-1R signaling by the non-homologous cytokines IL-34 and CSF-1.
The mechanism of shared but distinct CSF-1R signaling by the non-homologous cytokines IL-34 and CSF-1.
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DOI：
10.1016/j.bbapap.2012.04.012
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发表时间：
2012-07
影响因子：
3.2
通讯作者：
He, Xiaolin
中科院分区：
文献类型：
--
作者：
Liu, Heli;Leo, Cindy;Chen, Xiaoyan;Wong, Brian R.;Williams, Lewis T.;Lin, Haishan;He, Xiaolin
关键词：
白细胞介素-34（IL-34）和集落刺激因子-1（CSF-1）都通过CSF-1 R受体酪氨酸激酶进行信号传导，但它们没有序列同源性，并且它们的功能和信号传导活性不相同。我们报告了小鼠IL-34单独和与小鼠CSF-1 R的N-末端三个免疫球蛋白样结构域（D1-D3）复合的晶体结构。IL-34在结构上与其他螺旋造血细胞因子相关，但含有与四个共享螺旋整体相关的两个额外螺旋。非共价连接的IL-34同二聚体在螺旋束的侧面募集两个拷贝的CSF-1 R，其总体形状类似于CSF-1：CSF-1 R复合物，但CSF-1 R D2和D3之间的柔性接头允许这些结构域以不同角度夹持IL-34和CSF-1。IL-34：CSF-1 R界面的功能解剖表明，疏水相互作用而不是盐桥网络主导IL-34的生物活性。为了简并识别具有完全不同表面的两个配体，CSF-1 R显然利用了化学惰性表面的不同子集，这些子集可以被调整以适应不同的配体形状。IL-34和CSF-1之间的差异化信号传导可能是通过IL-34相对于CSF-1在受体识别位点的负协同性的相对热力学独立性以及疏水性的差异来实现的，所述疏水性的差异决定了与CSF-1：CSF-1 R复合物相比更稳定的IL-34：CSF-1 R复合物。
Interleukin-34 (IL-34) and colony stimulating factor-1 (CSF-1) both signal through the CSF-1R receptor tyrosine kinase, but they have no sequence homology, and their functions and signaling activities are not identical. We report the crystal structures of mouse IL-34 alone and in complex with the N-terminal three immunoglobulin-like domains (D1-D3) of mouse CSF-1R. IL-34 is structurally related to other helical hematopoietic cytokines, but contains two additional helices integrally associated with the four shared helices. The non-covalently linked IL-34 homodimer recruits two copies of CSF-1R on the sides of the helical bundles, with an overall shape similar to the CSF-1:CSF-1R complex, but the flexible linker between CSF-1R D2 and D3 allows these domains to clamp IL-34 and CSF-1 at different angles. Functional dissection of the IL-34:CSF-1R interface indicates that the hydrophobic interactions, rather than the salt bridge network, dominate the biological activity of IL-34. To degenerately recognize two ligands with completely different surfaces, CSF-1R apparently takes advantage of different subsets of a chemically inert surface that can be tuned to fit different ligand shapes. Differentiated signaling between IL-34 and CSF-1 is likely achieved by the relative thermodynamic independence of IL-34 vs. negative cooperativity of CSF-1 at the receptor-recognition sites, in combination with the difference in hydrophobicity which dictates a more stable IL-34:CSF-1R complex compared to the CSF-1:CSF-1R complex.
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DOI：
10.1107/s0907444999000839
发表时间：
1999-04
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Terwilliger TC;Berendzen J
通讯作者：
Berendzen J
影响因子：
64.5
作者：
SHERR, CJ;RETTENMIER, CW;STANLEY, ER
通讯作者：
STANLEY, ER
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
DOI：
10.1107/s0907444998003254
发表时间：
1998-09-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
Brunger, AT;Adams, PD;Warren, GL
通讯作者：
Warren, GL
影响因子：
12.4
作者：
Chihara, T.;Suzu, S.;Okada, S.
通讯作者：
Okada, S.