1.I.1.1.3
Nuclear Pore Complex, NPC, with 86 protein components.  NPCs mediate nucleocytoplasmic transport and gain transport selectivity through nucleoporin FG domains. Chug et al. 2015 reported a structural analysis of the frog FG Nup62•58•54 complex. It comprises a ≈13 nanometer-long trimerization interface with an unusual 2W3F coil, a canonical heterotrimeric coiled coil, and a kink that enforces a compact six-helix bundle. Nup54 also contains a ferredoxin-like domain. Chug et al. 2015 further identified a heterotrimeric Nup93-binding module for NPC anchorage. The quaternary structure alternations in the Nup62 complex, which were previously proposed to trigger a general gating of the NPC, are incompatible with the trimer structure. Chug et al. 2015 suggested that the highly elongated Nup62 complex projects barrier-forming FG repeats far into the central NPC channel, supporting a barrier that guards the entire cross section. The Sun1/UNC84A protein and Sun2/UNC84B may function redundantly in early HIV-1 infection steps and therefore influence HIV-1 replication and pathogenesis (Schaller et al. 2017).  The integral transmembrane nucleoporin Pom121 functionally links nuclear pore complex assembly to nuclear envelope formation (Antonin et al. 2005) and ensures efficient HIV-1 pre-integration complex nuclear import (Guo et al. 2018). Mechanosensing at the nuclear envelope by nuclear pore complex stretch activation involves cell membrane integrins (TC# 8.A.54) and SUN proteins, SUN1 and SUN2, in the nuclear membrane (Donnaloja et al. 2019). TMX2 is a thioredoxin-like protein that facilitates the transport of proteins across the nuclear membrane (Oguro and Imaoka 2019). Torsin ATPase deficiency leads to defects in nuclear pore biogenesis and sequestration of the myelokd leukemia factor 2, MLF2 (Rampello et al. 2020). Cdk1 (CDC2, CDC2.8A, CDKN1, P34CDC2) acts as a receptor for hepatitis C virus (HCV) in hepatocytes and facilitates its cell entry (Lupberger et al. 2011). G4C2 repeat RNA initiates a POM121-mediated reduction in specific nucleoporins (Coyne et al. 2020) (Pom121: acc# A8CG34). Defects in nucleocytoplasmic transport and accumulation of specific nuclear-pore-complex-associated proteins play roles in multiple neurodegenerative diseases, including C9orf72 Amyotrophic Lateral Sclerosis and Frontotemporal Dementia (ALS/FTD). Using super-resolution structured illumination microscopy, Coyne et al. 2020 have explored the mechanism by which nucleoporins are altered in nuclei isolated from C9orf72 induced pluripotent stem-cell-derived neurons (iPSNs). Of the 23 nucleoporins evaluated, they observed a reduction in a subset of 8, including key components of the nuclear pore complex scaffold and the transmembrane nucleoporin POM121. Reduction in POM121 appeared to initiate a decrease in the expression of seven additional nucleoporins, ultimately affecting the localization of the Ran GTPase and subsequent cellular toxicity in C9orf72 iPSNs. Thus, the expression of expanded C9orf72 ALS/FTD repeat RNA affects nuclear POM121 expression in the initiation of a pathological cascade affecting nucleoporin levels within neuronal nuclei and ultimately downstream neuronal survival (Coyne et al. 2020). Involved in the organization of the nuclear envelope, implicating EMD, SUN1 and A-type lamina (Gudise et al. 2011), but it also promotes breast cancer metastasis by positively regulating TGFbeta signaling (Kong et al. 2021). Nucleoporin POM121 signals TFEB-mediated autophagy via activation of the SIGMAR1/sigma-1 receptor chaperone by pridopidine (Wang et al. 2022). AI-based structural prediction empowers integrative structural analysis of human nuclear pores (Mosalaganti et al. 2022). With a molecular weight of approximately 120 MDa, the human NPC is one of the largest protein complexes. Its ~1000 proteins are taken in multiple copies from a set of about 30 distinct nucleoporins (NUPs). They can be roughly categorized into two classes. Scaffold NUPs contain folded domains and form a cylindrical scaffold architecture around a central channel. Intrinsically disordered NUPs line the scaffold and extend into the central channel where they interact with cargo complexes. The NPC architecture is highly dynamic. It responds to changes in nuclear envelope tension with conformational breathing that manifests in dilation and constriction movements. AI-based predictions generated an extensive repertoire of structural models of human NUPs and their subcomplexes (Mosalaganti et al. 2022). The 70-MDa atomically resolved model covers >90% of the human NPC scaffold. It captures conformational changes that occur during dilation and constriction. It also reveals the precise anchoring sites for intrinsically disordered NUPs, the identification of which is a prerequisite for a complete and dynamic model of the NPC. This exempli-fies how AI-based structure predictions may accelerate the elucidation of subcellular architecture at atomic resolution. The nucleocytoplasmic transport protein, importin-5, plays a role in the crosstalk between activin and BMP signalling in human testicular cancer cell lines (Radhakrishnan et al. 2023). Viral targeting of importin alpha-mediated nuclear import blocks innate immunity (Vogel et al. 2023).  The nuclear pore protein POM121 regulates subcellular localization and transcriptional activity of PPARgamma. (Yu et al. 2024).  Stabilization of KPNB1 by deubiquitinase USP7 promotes glioblastoma progression through the YBX1-NLGN3 axis (Li et al. 2024). Retroviral hijacking of host transport pathways are used for viral genome nuclear export (Behrens and Sherer 2023).  Biallelic variants in AAAS, encoding ALADIN, cause triple A syndrome (Allgrove syndrome). Triple A syndrome, characterized by alacrima, achalasia, and adrenal insufficiency, often includes progressive demyelinating polyneuropathy and other neurological complaints (Smits et al. 2024).  The NUP210 gene is upregulated in several solid tumors, this is true for acute myeloid leukemia (AML), and this may promote the malignant behavior of AML cells by upregulate HOXA9 gene expression (Wu et al. 2025). MiR-20a-5p inhibits bladder cancer proliferation and migration by targeting KPNA2 (Ye et al. 2025).