A lattice model of the nuclear pore complex

Abstract

The nuclear pore complex (NPC) is one of the largest protein machines in the cell and forms the sole conduit for nucleocytoplasmic transport in eukaryotes. The NPC is composed of an eightfold radially symmetric scaffold of architectural proteins that anchor a set of phenylalanine-glycine (FG) repeat proteins that form the transport barrier. As a step toward elucidating the molecular architecture of the NPC, we solved the structure of nucleoporin 85 (Nup85) in complex with Seh1, a module in the heptameric Nup84 subcomplex. We define a new tripartite protein element, the ancestral coatomer element ACE1, which Nup85 specifically shares with several other nucleoporins and vesicle coat proteins. We predicted and verified functional sites on nucleoporin ACE1 members based on analogy to ACE1 interactions that propagate the COPII vesicle coat. Thus, we provide the first experimental evidence for evolution of the NPC and vesicle coats from a common ancestor. We propose that the NPC structural scaffold, like vesicle coats, is a polygonal network composed of vertex and edge elements that forms a molecular lattice upon which additional nucleoporins assemble. Here we further discuss our findings and elaborate on our lattice model of the nuclear pore complex.

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Acknowledgements

This work was supported by NIH Grant GM77537 (Thomas U. Schwartz), a Pew Scholar Award (Thomas U. Schwartz), a Koch Fellowship Award (Stephen G. Brohawn) and a Vertex Scholarship (Stephen G. Brohawn).

Figures and Tables

Figure 1 A lattice model of the NPC. Sec31, Nup85, Nup145C, Nup84 and Nic96 ACE1 proteins are colored with crowns blue, trunks orange and tail modules green. Other protein folds are shown in grey. (A) Schematic organization of the COPII outer vesicle coat. On the left, an edge element consisting of two Sec31·Sec13 heterodimers is shown. Two Sec31 molecules interact crown·crown. On the right, an entire COPII cuboctahedron coat composed of 24 edge elements is shown unwrapped and laid flat.11 Vertex elements are formed where two Sec31 and two Sec13 β-propellers interact. (B) Alternative organizations of the NPC lattice. On the left, the Nup84 subcomplex is shown in schematic fashion illustrating how ACE1 interactions organize the Y-shaped structure. Nup145C and Nup84 also interact crown·crown. On the right, the entire NPC structural scaffold is shown unwrapped and laid flat. Two rings of the Nup84 subcomplex form the lattice of the NPC scaffold either with an intervening ring of the Nic96 subcomplex (i) or alone (ii). Both the identity and organization of the vertex elements and the Nic96 subcomplex in the pore lattice are unknown and are shown half-transparent. The presented organization is not meant to predict relative positions of proteins or the structure per se, but rather emphasizes the principally similar lattice organization of NPCs and vesicle coats.

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