Molecular mechanisms underlying the evolution of the slp76 signalosome.
Molecular mechanisms underlying the evolution of the slp76 signalosome.
复制标题
slp76信号体进化的分子机制
DOI：
10.1038/s41598-017-01660-0
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发表时间：
2017-05-04
影响因子：
4.6
通讯作者：
Li Y
中科院分区：
文献类型：
--
作者：
Qu X;Lan X;Deng C;Zhou J;Du J;Huang S;Li Y
明确定义的哺乳动物slp 76-信号体对于T细胞免疫应答至关重要，但slp 76-信号体是否存在于无脊椎动物中以及它如何进化仍然未知。在这里，我们调查slp 76-信号体从进化的角度在文昌鱼Branchiostoma belcheri（bb）。我们证明了文昌鱼中存在slp 76信号体组分bbslp 76、bbGADS和bbItk，bbslp 76与bbGADS和bbItk相互作用，但文昌鱼和人的slp 76信号体组分之间的相互作用方式存在差异。具体地，bbslp 76具有独特的WW-domain，其阻断其与hItk的结合并降低TCR诱导的酪氨酸磷酸化和NFAT活化。WW-domain的缺失使bbslp 76和hPLCγ1之间的组成性关联转变为TCR增强的关联。在slp 76信号体中，slp 76与PLCγ1的相互作用最为保守，Itk与slp 76的结合由组成型逐渐演变为刺激调节型。slp 76信号体分子的序列比对和三维结构分析表明，slp 76由于缺失了WW结构域和多个低复杂性区域（LCR）而进化成了一个更大的蛋白质，从而为slp 76信号体的成核提供了更大的空间。总之，通过缺失WW-domain和操纵LCR，slp 76-信号体从刚性的和刺激不敏感的演变为更灵活的和刺激响应的复合物。
The well-defined mammalian slp76-signalosome is crucial for T-cell immune response, yet whether slp76-signalosome exists in invertebrates and how it evolved remain unknown. Here we investigated slp76-signalosome from an evolutionary perspective in amphioxus Branchiostoma belcheri (bb). We proved slp76-signalosome components bbslp76, bbGADS and bbItk are present in amphioxus and bbslp76 interacts with bbGADS and bbItk, but differences exist between the interaction manners within slp76-signalosome components of amphioxus and human (h). Specifically, bbslp76 has a unique WW-domain that blocked its association with hItk and decreased TCR-induced tyrosine-phosphorylation and NFAT-activation. Deletion of WW-domain shifted the constitutive association between bbslp76 and hPLCγ1 to a TCR-enhanced association. Among slp76-signalosome, the interaction between slp76 and PLCγ1 is the most conserved and the binding between Itk and slp76 evolved from constitutive to stimulation-regulated. Sequence alignment and 3D structural analysis of slp76-signalosome molecules from keystone species indicated slp76 evolved into a more unfolded and flexible adaptor due to lack of WW-domain and several low-complexity-regions (LCRs) while GADS turned into a larger protein by a LCR gain, thus preparing more space for nucleating the coevolving slp76-signalosome. Altogether, through deletion of WW-domain and manipulation of LCRs, slp76-signalosome evolves from a rigid and stimulation-insensitive to a more flexible and stimulation-responding complex.