How the TREX-2 complex associates with the nuclear pore.

The mammalian nuclear pore complex (NPC), approximately 120 MDa, is the gateway regulating nucleocytoplasmic traffic ^[2]. Previous studies have resolved the structure of the NPC scaffold in considerable detail, but the transport machinery composed of numerous disordered FG nucleoporins remains difficult to visualize directly, appearing even as a "hole" in high-resolution tomograms and computational structures ^[2]. Meanwhile, the role of the NPC is not limited to the movement of materials in and out; it is also thought to participate in nuclear organization and the coordination of genetic information transfer to the cytoplasm, being closely linked to gene expression regulation ^[1]. Therefore, which molecules actually constitute the NPC—which components bind only transiently and which are stable built-in modules—remains a key obstacle to understanding its transport function.

This study combined cryo-electron tomography, cross-linking mass spectrometry, and AI-assisted integrative modeling to obtain a substantially expanded structure of the human NPC. The researchers resolved the molecular arrangement of four components—TPR, NUP153, NUP50, and ZC3HC1—and confirmed that five proteins—TMEM209, SMPD4, GANP, Centrin-2, and ENY2—constitute components of the NPC. Most unexpectedly, three core members of the TREX-2 mRNA export complex—GANP, Centrin-2, and ENY2—are not merely transient visitors near the nuclear pore but are built directly into the nuclear ring.

The paper thereby makes a substantive advance over existing knowledge: TREX-2 is no longer regarded as a transiently associated export factor but is repositioned as a built-in module of the NPC, situated opposite the cytoplasmic NUP214 mRNA export platform. The study also redefined the molecular composition of the inner ring, nuclear ring, and nuclear basket, providing a structural basis for directly coupling TREX-2-mediated messenger ribonucleoprotein particle (mRNP) remodeling with NPC-facilitated transport. However, the current evidence mainly establishes spatial links and points to mechanistic directions; the specific coupling steps and their functional causal chains still require subsequent experimental validation.