Mishra Ankur, Van der Giessen Erik, Onck Patrick R
Zernike Institute for Advanced Materials, University of Groningen, Groningen, the Netherlands.
Zernike Institute for Advanced Materials, University of Groningen, Groningen, the Netherlands.
Biophys J. 2025 Jan 21;124(2):215-226. doi: 10.1016/j.bpj.2024.11.3313. Epub 2024 Nov 26.
The nuclear pore complex (NPC) is responsible for the selective transport of biomolecules in and out of the nucleus. This selective feature is achieved through intrinsically disordered proteins, FG-Nups, that are anchored to the inner wall of the NPC. Cargo smaller than approximately 5 nm can rapidly diffuse through the NPC whereas larger cargo is increasingly slowed down. Larger cargos bound to chaperone proteins (from the karyopherin or Kap family) can still be transported due to nonspecific interactions with the FG-Nups. Although various mechanisms for the transport of Kaps have been proposed, a consensus has still to be reached. Here, we conducted a coarse-grained molecular dynamics study to shed light on Kap translocation through NPCs. We investigated the effect of Kap surface charge and hydrophobicity on the transport rate. We found that the negative charge of the Kaps is essential for transport whereas Kap hydrophobicity of the transport particle aids in the translocation. Interestingly, our results indicate that the positive net charge of the nuclear Nups (especially Nup1) is instrumental for the transport of Kaps, revealing a (previously proposed) gradient of increasing binding affinity of the Kaps with FG-Nups from the cytoplasm to the nucleus.
核孔复合体（NPC）负责生物分子进出细胞核的选择性运输。这种选择性是通过内在无序蛋白（FG-Nups）实现的，这些蛋白锚定在NPC的内壁上。小于约5纳米的货物可以迅速通过NPC扩散，而较大的货物则越来越慢。与伴侣蛋白（来自核转运蛋白或Kap家族）结合的较大货物由于与FG-Nups的非特异性相互作用仍可被运输。尽管已经提出了多种Kap运输机制，但仍未达成共识。在这里，我们进行了一项粗粒度分子动力学研究，以阐明Kap通过NPC的转运。我们研究了Kap表面电荷和疏水性对运输速率的影响。我们发现，Kap的负电荷对运输至关重要，而运输颗粒的Kap疏水性有助于转运。有趣的是，我们的结果表明，核孔蛋白（尤其是Nup1）的正净电荷对Kap的运输至关重要，揭示了（先前提出的）Kap与FG-Nups从细胞质到细胞核的结合亲和力增加的梯度。
