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Checkpoint architecture
How can you use the same number of pieces to form two rings that fit inside each other? Martin Beck's group in Heidelberg set out to find the answer to this nuclear pore riddle.
Each cell’s precious genomic cargo is safely ensconced in a nuclear membrane that acts as an intracellular border, separating the contents of the nucleus from the rest of the cellular landscape. Like a border between two countries, it’s dotted with checkpoints, called nuclear pore complexes (NPCs) – massive structures made out of hundreds of individual proteins of more than 30 different types, many of which are present in multiple copies.
The NPC proteins not only give shape to the pore, creating a channel through which other cellular components can move, but also govern which migrating molecules are allowed to pass.
To work out how these dual tasks are achieved, biologists need detailed information about the structure of individual NPC proteins, and how they’re assembled into the multi-protein checkpoint. Martin Beck, group leader at EMBL Heidelberg, is busy working on these problems.
The work of many labs around the world has revealed the large-scale organisation of the NPC, which comprises three rings: a nuclear ring (NR) that faces inside the nucleus, a cytoplasmic ring (CR) that faces away from the nucleus, and an inner ring (IR) sandwiched between the other two.
In previous work, Beck and colleagues showed that both the NR and CR consist of two concentric circles, each comprising 8 copies of a Y-shaped protein complex. But this posed a new question, says Beck. “If you use the same number of the same building block, how can you form two rings of slightly different diameters that can fit inside each other?”
A new paper by Beck and colleagues, published in Nature, provides an answer. “This geometric problem is essentially solved by flexible hinges in the Y-complex, which allows it to extend or compress a bit,” says Beck. But what determines what shape the Y-complex adopts? Beck and colleagues found that a specific NPC protein, called Nup358, has a key role in regulating how the Y-complexes assemble, especially in the CR.
When the scientists impaired the cell’s ability to produce Nup358, the outer concentric ring in the CR failed to assemble, although the other ring in the CR, and both rings in the NR, remained intact. This, says Beck, shows that NPC proteins can affect how identical components can be assembled into different structures, with different functions – a form of “cellular moonlighting”, as Beck describes it.
Other research has suggested that Nup358 is only expressed during certain stages of embryonic development, and in certain cell types. This raises the possibility that Nup358, by affecting the structure of Y-complex rings in the NR and CR, could influence the cell’s behaviour. In fact there are already hints it may play a role in some cancers, and so better understanding Nup358 could have therapeutic implications. “That could be the ultimate outcome of this work,” says Beck, “but it is still quite far off.”
