The nuclear pore complex: structure and function

Abstract

Forkhead box P3 (FOXP3), a gene member of the forkhead/winged-helix family of transcription regulators, is Nuclear pore complexes (NPCs) are large multi-protein complexes, which are embedded in the nuclear envelope and which are regulating the molecular exchange between the nucleus and the cytoplasm. While electron microscopy and cryo-electron tomography studies have provided high-resolution pictures of the NPC structure as entity, the challenge nowadays is to elucidate the organization and the functions of nuclear pore proteins (nucleoporins or Nups) inside and outside the NPC. Nucleoporins are not only involved in nucleocytoplasmic transport, but in an increasing number of other cellular processes, such as kinetochore organization, cell cycle regulation, DNA repair, and gene expression. The implication of nucleoporins in these diverse processes links them also to a wide variety of human diseases, such as cancer and autoimmune diseases. Here we review the progress made in defining the molecular arrangement of nucleoporins within the NPC and use the example of Nup153 to illustrate the versatility of individual nucleoporins and their implication in various human diseases.

Mechanosensing at the Nuclear Envelope by Nuclear Pore Complex Stretch Activation and Its Effect in Physiology and Pathology

“…According to cryo-electron microscopy and tomography images, NPCs consist of an 8-fold symmetric central scaffold, eight cytoplasmic filaments, and eight nucleoplasmic filaments, resulting in a rotational symmetry (Lezon et al, 2009; Knockenhauer and Schwartz, 2016). The nucleoplasmic filaments co-join in a distal ring to form the so-called nuclear basket structure (Walther et al, 2001; Krull et al, 2004; Wälde and Kehlenbach, 2010; Moussavi-Baygi et al, 2011; Duheron and Fahrenkrog, 2015). The 8-fold rotational symmetry appears to maximize the bending stiffness of each of the eight NPC spokes, thus guaranteeing structural stability during the transport of large cargoes (Rowat et al, 2005).…”

“…Cryo-electron tomography analysis indicates that both nucleoplasmic and cytoplasmic ring complexes (dark green in Figure 1) are characterized by the repetition of so-called Y subcomplexes (0.5–0.75 MDa) consisting of a stem base, which joins both the small and the large arm in a central hub element. Individual Y-shaped complexes are arranged head-to-tail into two antiparallel, ring-like octameric entities on both the cytoplasmic and nuclear face of the NPC (Duheron and Fahrenkrog, 2015; Eibauer et al, 2015). Both the nucleoplasmic and cytoplasmic ring complex structures consist of a total of 32 Y complexes assembled into two eight-membered, concentric and reticulated rings, which are stacked with a slight offset and differ only slightly in diameter (Von Appen et al, 2015; Hoelz et al, 2016; Knockenhauer and Schwartz, 2016).…”

“…Another constituent of the NPC’s nuclear basket is Nup153 (1475 amino acids) composed of three main domains: (i) the N-terminal domain spanning about 600 amino acids (Duheron et al, 2014), which consists of a nuclear localization signal, a nuclear envelope targeting cassette, an NPC association region and a RNA binding domain (Ball and Ullman, 2005; Al-Haboubi et al, 2011; Duheron and Fahrenkrog, 2015); (ii) a central domain spanning about 250 amino acids consisting of four or five zinc fingers, which tie Nup153 to the distal ring (Duheron et al, 2014); (iii) a C-terminal domain consisting of around 600 amino acids containing ∼30 FxFG-repeats (Walther et al, 2001). The N-terminal domain is predominantly detected closer to the membrane, the zinc-finger domain is found at the distal ring, whereas the Nup153’s FG-repeats is detected all over the nuclear basket and occasionally on the cytoplasmic side (Ball and Ullman, 2005; Duheron and Fahrenkrog, 2015). The nature of Nup153 localization is not fully elucidated yet and several scenarios have been proposed to explain how a mobile Nup could tether a stable component such as Tpr.…”

Nucleoporin 153 regulates estrogen-dependent nuclear translocation of endothelial nitric oxide synthase and estrogen receptor beta in prostate cancer

“…Specifically, it has been recently demonstrated that Nup153 represents a new class of global chromatin-binding proteins regulating the spatial organization of chromosomes associating at very high density with transcriptionally active regions [ 1 , 2 ]. NUPs, including Nup153, appear to be implicated in a large number of disorders, such as cardiomyopathy associated to muscular dystrophy [ 2 ], autoimmune disease and cancer [ 3 , 4 ]. In this regard, several reports established that NUPs regulate cancer through different mechanisms based either on the import of DNA repair proteins [ 5 ] or gene regulation [ 3 ].…”

t(11;12)(p15;q13) NUP98/HOXC11::t(11;12)(p15;q13) NUP98/HOXC13

“…The 98 kDa nucleoporin contains a Gly-Leu-Phe-Gly (GLFG and FG) repeat in Nterm, a GLEBS-like motif (which binds RAE1), and a RNA binding motif in C-term. NUP98 is involved in nuclear import/export, mitotic progression, and regulation of gene expression (Duheron and Fahrenkrog, 2015).…”