NAP1 与 NDP52 和 TAX1BP1 的 SKICH 结构域相互作用的机制见解。
Mechanistic insights into the interactions of NAP1 with the SKICH domains of NDP52 and TAX1BP1.
机构信息
State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200032 Shanghai, China.
State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200032 Shanghai, China
出版信息
Proc Natl Acad Sci U S A. 2018 Dec 11;115(50):E11651-E11660. doi: 10.1073/pnas.1811421115. Epub 2018 Nov 20.
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.
NDP52 和 TAX1BP1 是两个含有 SKIP 羧基端同源（SKICH）结构域的自噬受体，在选择性自噬中发挥着关键作用。NDP52 和 TAX1BP1 的自噬功能受到 TANK 结合激酶 1（TBK1）的调节，TBK1 可能通过衔接蛋白 NAP1 与之结合。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 磷酸化所诱导的效应，仍不清楚。在这里，我们报道了 NDP52 和 TAX1BP1 的 SKICH 区域与 NAP1 复合物的原子结构，这不仅揭示了 NAP1 与 NDP52 和 TAX1BP1 的 SKICH 结构域特异性相互作用的机制基础，还揭示了 SKICH 结构域的结合模式。此外，我们发现 NDP52 和 TAX1BP1 的 SKICH 结构域具有与 NAP1 相互作用的通用结合模式。最后，我们还根据 NAP1 与 NDP52 和 TAX1BP1 的 SKICH 结构域的相互作用，评估了目前已知的 TBK1 介导的磷酸化位点。总之，我们的研究结果为 NAP1 与 NDP52 和 TAX1BP1 的相互作用提供了机制见解，对于进一步理解这些蛋白在选择性自噬中的功能具有重要意义。
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