Nuclear pore complexes

Abstract

What are they? Nuclear pore complexes (NPCs) are often referred to as the ‘gatekeepers of the nucleus’, being responsible for regulating the molecular traffic – from ions to ribosomes – between the nucleoplasm and the cytoplasm. A typical vertebrate nucleus has about 5,000 NPCs scattered over its surface.What do they look like? A picture is worth twice the length of this article (Figure 1Figure 1). All eukaryotes have these impressive structures: vertebrates have the Cadillac model (∼125 MDa) and yeast a sportier version (∼50 MDa). In spite of their immense size, these structures are made of a relatively small number of proteins – about 30 – the so-called nucleoporins or nups. Defining an NPC ‘interactome’ is paramount to understanding its function. A number of groups are contributing to this effort, so check back for updates in the near future.Figure 1A model of the vertebrate NPC within a cross sectional view of the nuclear envelope membrane (gray).The NPC is constructed with a central core consisting of ring structures (light blue and purple) from which eight spokes radiate to surround a central transporter (pink). Extending from the core are cytoplasmic filaments (red) and a nuclear basket (blue). (Model kindly provided by M. Rout and J. Aitchison.)View Large Image | View Hi-Res Image | Download PowerPoint SlideHow do they work? In the last 10 years, a clearer picture has developed for the NPC's role in nuclear transport. A family of soluble proteins called karyopherins or kaps – a.k.a. importins or exportins – recognize signal-containing cargoes and then bind to the NPC. Translocation then ensues with directionality and the energy for repeated rounds of transport provided by the GTPase Ran.How do cargoes move through the NPC? This remains a major unresolved issue. Models addressing this must consider the massive number of kap–cargo complexes that go through the NPC every second, and the NPC's large number of kap-binding sites. The field has settled on the idea that NPCs transport cargoes by a binding-diffusion mechanism rather than, for example, a molecular motor. One model suggests kaps are entrapped by nup-based tentacles, counteracting the entropically unfavorable process of diffusion through the NPC. The kaps are proposed to ping-pong between multiple low-affinity sites until reaching higher-affinity sites in the target compartment. Another model proposes that the nups form a hydrophobic meshwork that is selectively permeable to kaps. Still to be explained is why some kaps preferentially interact with certain nups. This suggests that the trip through the NPC is not the same for all the kaps and raises the possibility that these different traffic lanes can be differentially controlled.Are NPCs just for transport? No. Recently, a number of intriguing observations have opened our eyes to other functions of the NPC. Some reports suggest that traveling through the NPC gate may not necessarily be a passive event for the cargo molecules, and that some are ‘stamped’ with the ubiquitin-related modifier SUMO as they travel through. This modification likely helps determine the fate of the cargo after it enters the nucleus, including its destination and half-life.Anything else? NPCs also appear to control the spatial orientation and transcriptional activity of chromatin. In yeast, NPCs, like puppeteers, influence telomeric silencing via fiber-forming proteins emanating from their nucleoplasmic face. Recent studies have also shown that tethering a gene to the NPC can prevent its repression by creating a boundary between the gene and surrounding silenced heterochromatin. Both observations lend support to the enduring idea that the NPC, through association with the underlying chromatin, regulates gene expression.More Madness? Nups have begun to show up at some surprising locations. During mitosis in vertebrates, a number of nups are recruited to kinetochores. The link to kinetochores goes beyond this. At least two proteins that function in the spindle assembly checkpoint, Mad1 and Mad2, reside at NPCs during interphase. What they're doing there is still anyone's guess. Like the examples mentioned above, these observations show that our understanding of how the NPC influences nuclear physiology is just beginning to blossom.