Molecule of the Month: Importins

Inside your cells, the process of protein synthesis is separated into two compartments. The first half of the job, when DNA is transcribed into RNA, is performed in the nucleus. The second half is then performed outside the nucleus, when ribosomes translate the RNA to construct proteins in the cytoplasm. This separation requires a continuous traffic of molecules: new RNA molecules must be transported out of the nucleus and nuclear proteins, such as newly-synthesized histones or polymerases, must be transported back into the nucleus. Huge tube-shaped nuclear pores act as the highway connecting the nucleus and the cytoplasm, and importins and exportins (collectively known as karyopherins) ferry molecules back and forth through the pore.

Importins transport thousands of different proteins into the nucleus to perform the many tasks of storing, reading, and repairing the genome. However, it would be far too costly to design a special importin to carry each one inside. Instead, many nuclear proteins are built with a special tag—a short sequence called the nuclear localization signal—that tells the transport machinery to carry the protein into the nucleus. Importins recognize this signal, bind to the protein, and transport it through the nuclear pore.

The importin complex shown here (built from three separate PDB entries) transports proteins with nuclear localization signals. At the top in blue is importin-beta (PDB entry 1qgk ). It is the engine of the complex, recognizing nuclear pores and moving through them. It wraps around the end of importin-alpha, shown at the center in green (PDB entry 1ee5 ). Importin-alpha is an adapter molecule that connects importin-beta with the cargo. In this picture, the cargo is nucleoplasmin, shown at the bottom in yellow (PDB entry 1k5j ), a chaperone protein that is important in nucleosome assembly. Notice how the extended nuclear localization signal of this cargo is gripped by importin-alpha.

Once the importin-beta/importin-alpha/cargo complex gets inside the nucleus, the cargo must be released and the importins must be recycled back to the cytoplasm. The Ran protein, shown here in light red, is responsible for releasing the cargo. It binds to importin-beta and causes a significant change in shape, leading to the release of importin-alpha and the cargo. Then, the complex of importin-beta and Ran (shown on the left, PDB entry 2bku) travels back through the pore. Outside, a GTP molecule in Ran (shown in bright red) is cleaved and the Ran dissociates, leaving importin-beta ready to carry the next cargo protein inside. Importin-alpha can't get back to the cytoplasm by itself, so it gets some help from CAS (a nuclear export factor), shown here on the right in purple (PDB entry 1wa5 ). CAS is similar to importin-beta, but moves through the nuclear pore in the opposite direction. It binds to importin-alpha and Ran and carries them out of the nucleus. Then, a similar cleavage of the GTP in Ran releases importin-alpha for another round of transport.