Inner Nuclear Membrane Proteins are Actively Imported

This is the newest from the Blobel lab.

Note to all "they've discovered everything" types: this finding shows how much we know about how cells operate.

Background: As I've described before the nucleus and the cytoplasm are two cellular compartments that are kept apart by the Nuclear Pore Complex (NPC). This mega-assembly of proteins is the gate (or the bouncer) of the nucleus - pass it and you can gain access to the nucleus from the cytoplasm (or vice versa). NPCs sit in the nuclear envelope, an extension of the ER that covers the chromosomes.

Nuclear proteins are synthesized in the cytoplasm. To cross the NPC and thus gain access to the nucleoplasm, these proteins are equiped with a nuclear localization sequence (NLS) that recruits special proteins called "Karyopherins" (alpha/beta importin in the diagram). Karyopherins are like VIPs, they can side step the bouncer and thus escort the proteins into the nucleus. Once inside, the importins release their guest, bind to the small G-protein Ran in it's GTP bound configuration, and are exported back out of the nucleus. Once out Ran hydrolyses its GTP into GDP + phosphate.

The whole import pathway is thus maintained by a Ran-GTP gradient across the membrane and requires energy (in the form of GTP).

But there are exceptions to this active import process. Smaller proteins (< 30 KDa) freely diffuse through the NPC, and it was thought that proteins found in the inner-nuclear-membrane could also diffuse across this barrier.

But now a new paper from the Blobel lab demonstrates that at least some inner-nuclear membrane proteins in yeast can only enter the nucleus by recruiting karyopherins. Since these karyopherins require a Ran-GTP gradient, this import process requires energy. So inner-nuclear-membrane proteins (in this diagram the red blob) may act just like most proteins - they can't just waltz into the nucleus without a VIP pass.

The NPC may not let just any old membrane protein into the inner-nuclear-envelope, and thus the composition of the inner-nuclear-membrane is more tightly regulated than we once believed. In other words this component of the ER (the inner-nuclear-membrane) may be more differentiated than we one thought.

Ref:

Megan C. King, C. Patrick Lusk and Günter Blobel
Karyopherin-mediated import of integral inner nuclear membrane proteins
Nature (06) AOP