Abstract
Nuclear pore complexes (NPCs) form gateways for material transfer across the nuclear envelope of eukaryotic cells. Disordered proteins, rich in phenylalanine-glycine repeat motifs (FG-nups), form the central transport channel. Understanding how nups are arranged in the interior of the NPC may explain how NPC functions as a selectivity filter for transport of large molecules and a sieve-like filter for diffusion of small molecules (< or ). We employed molecular dynamics to model the structures formed by various assemblies of one kind of nup, namely the 609-aa-long FG domain of Nsp1 (Nsp1-FG). The simulations started from different initial conformations and geometrical arrangements of Nsp1-FGs. In all cases Nsp1-FGs collectively formed brush-like structures with bristles made of bundles of 2–27 nups, however, the bundles being cross-linked through single nups leaving one bundle and joining a nearby one. The degree of cross-linking varies with different initial nup conformations and arrangements. Structural analysis reveals that FG-repeats of the nups not only involve formation of bundle structures, but are abundantly present in cross-linking regions where the epitopes of FG-repeats are highly accessible. Large molecules that are assisted by transport factors (TFs) are selectively transported through NPC apparently by binding to FG-nups through populated FG-binding pockets on the TF surface. Therefore, our finding suggests that TFs bind concertedly to multiple FGs in cross-linking regions and break-up the bundles to create wide pores for themselves and their cargoes to pass. In addition, the cross-linking between Nsp1-FG bundles, arising from simulations, is found to set a molecular size limit of < for passive diffusion of molecules. Our simulations suggest that the NPC central channel, near the periphery where tethering of nups is dominant, features brush-like moderately cross-linked bundles, but in the central region, where tethering loses its effect, features a sieve-like structure of bundles and frequent cross-links.
Highlights
Nuclear pore complexes (NPCs) are large protein assemblies embedded in the nuclear membrane that provide the only conduit for exchange of molecules between cytoplasm and nucleoplasm, a process defined as nucleocytoplasmic transport (NCT)
Each a complex made of many proteins, assure traffic into and out of the nucleus through highly selective transport: small biomolecules can pass unhindered, whereas large biomolecules need to associate with proteins called transport factors, to pass
Little is known about how the nuclear pore complexes function, a key impediment to observation being their huge size and the disordered nature of the pore interior
Summary
Nuclear pore complexes (NPCs) are large protein assemblies embedded in the nuclear membrane that provide the only conduit for exchange of molecules between cytoplasm and nucleoplasm, a process defined as nucleocytoplasmic transport (NCT). While the membrane bound nucleus of a eukaryotic cell protectively envelopes the genetic material, separating it from the cytoplasm, processes such as DNA transcription require access to the genetic material in the interior of the nucleus by a myriad of molecules, including large molecules such as proteins. NPCs are giant complexes having molecular masses ranging from ,65 MDa (in yeast) to ,125 MDa (in higher eukaryotes) that are made of copies of 30 different proteins termed nucleoporins (nups) [2,3,4,5]. The scaffold of the NPC is formed by two protein subcomplexes that, through linker proteins, anchor a set of FG-containing nups [6]. The NPC forms a multi-protein complex of nearly ,450 proteins [4,5,6,7]
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