Mechanistic insights into the interactions of NAP1 with the SKICH domains of NDP52 and TAX1BP1
Mechanistic insights into the interactions of NAP1 with the SKICH domains of NDP52 and TAX1BP1
复制标题
对 NAP1 与 NDP52 和 TAX1BP1 的 SKICH 结构域相互作用的机制见解。
DOI：
10.1073/pnas.1811421115
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发表时间：
2018-12-11
影响因子：
11.1
通讯作者：
Pan, Lifeng
中科院分区：
文献类型：
--
作者：
Fu, Tao;Liu, Jianping;Pan, Lifeng
NDP52和TAX1BP1是两个含有SKICH结构域的自噬受体，它们在选择性自噬中起着关键作用。NDP52和TAX1BP1的自噬功能受TANK-BINK 1(TANK-BINDING KEK1)的调节，该蛋白可能通过接头NAP1与其结合。然而，NAP1与NDP52和TAX1BP1相互作用的分子机制，以及TBK1介导的NDP52和TAX1BP1磷酸化的影响仍然不清楚。在这里，我们报道了NDP52和TAX1BP1与NAP1络合物中SKICH区域的原子结构，这不仅揭示了NAP1与NDP52和TAX1BP1的SKICH结构域相互作用的机制基础，而且揭示了SKICH结构域的结合模式。此外，我们还发现NDP52和TAX1BP1的SKICH结构域与NAP1有一个共同的结合模式。最后，我们还根据NDP52和TAX1BP1与NAP1的相互作用，评估了目前已知的TBK1介导的NDP52和TAX1BP1的SKICH结构域的磷酸化位点。总之，我们的发现为NAP1与NDP52和TAX1BP1的相互作用提供了机械性的见解，并对进一步了解这些蛋白在选择性自噬中的功能有价值。
NDP52 and TAX1BP1, two SKIP carboxyl homology (SKICH) domain-containing autophagy receptors, play crucial roles in selective autophagy. The autophagic functions of NDP52 and TAX1BP1 are regulated by TANK-binding kinase 1 (TBK1), which may associate with them through the adaptor NAP1. However, the molecular mechanism governing the interactions of NAP1 with NDP52 and TAX1BP1, as well as the effects induced by TBK1-mediated phosphorylation of NDP52 and TAX1BP1, remains elusive. Here, we report the atomic structures of the SKICH regions of NDP52 and TAX1BP1 in complex with NAP1, which not only uncover the mechanistic bases underpinning the specific interactions of NAP1 with the SKICH domains of NDP52 and TAX1BP1 but also reveal the binding mode of a SKICH domain. Moreover, we uncovered that the SKICH domains of NDP52 and TAX1BP1 share a general binding mode to interact with NAP1. Finally, we also evaluated the currently known TBK1-mediated phosphorylation sites in the SKICH domains of NDP52 and TAX1BP1 on the basis of their interactions with NAP1. In all, our findings provide mechanistic insights into the interactions of NAP1 with NDP52 and TAX1BP1, and are valuable for further understanding the functions of these proteins in selective autophagy.