Whatever you are doing, whether it is driving a car, going for a jog, or even at your laziest, eating chips and watching TV on the couch, there is an entire suite of molecular machinery inside each of your cells hard at work. That machinery, far too small to see with the naked eye or even with many microscopes, creates energy for the cell, manufactures its proteins, makes copies of its DNA, and much more.
Among those pieces of machinery, and one of the most complex, is something known as the nuclear pore complex (NPC). The NPC, which is made of more than 1,000 individual proteins, is an incredibly discriminating gatekeeper for the cell’s nucleus, the membrane-bound region inside a cell that holds that cell’s genetic material. Anything going in or out of the nucleus has to pass through the NPC on its way.
The NPC’s role as a gatekeeper of the nucleus means it is vital for the operations of the cell. Within the nucleus, DNA, the cell’s permanent genetic code, is copied into RNA. That RNA is then carried out of the nucleus so it can be used to manufacture the proteins the cell needs. The NPC ensures the nucleus gets the materials it needs for synthesizing RNA, while also protecting the DNA from the harsh environment outside the nucleus and enabling the RNA to leave the nucleus after it has been made.
“It’s a little like an airplane hangar where you can repair 747s, and the door opens to let the 747 come in, but there’s a person standing there who can keep a single marble from getting out while the doors are open,” says Caltech’s André Hoelz, professor of chemistry and biochemistry and a Faculty Scholar of the Howard Hughes Medical Institute. For more than two decades, Hoelz has been studying and deciphering the structure of the NPC in relation to its function. Over the years, he has steadily chipped away at its secrets, unraveling them piece by piece by piece by piece.
The implications of this research are potentially huge. Not only is the NPC central to the operations of the cell, it is also involved in many diseases. Mutations in the NPC are responsible for some incurable cancers, for neurodegenerative and autoimmune diseases such as amyotrophic lateral sclerosis (ALS) and acute necrotizing encephalopathy, and for heart conditions including atrial fibrillation and early sudden cardiac death. Additionally, many viruses, including the one responsible for COVID-19, target and shutdown the NPC during the course of their lifecycles.
Now, in a pair of papers published in the journal Science, Hoelz and his research team describe two important breakthroughs: the determination of the structure of the outer face of the NPC and the elucidation of the mechanism by which special proteins act like a molecular glue to hold the NPC together.
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