Nuclear protein transport pathways

Nuclear proteins like transcription factors and ribosomal proteins are synthesized in the cytoplasm and have to be transported into the nucleus to fulfill their functions. The transport of proteins >20-60 kD through the nuclear pore complex (NPC) into the nucleus is an active, energy-requiring process. Transport substrates are recognized by their transport proteins via certain signals. The best-characterized protein import pathway is the 'classical' nuclear localization signal-dependent pathway with importin alpha and beta carrying the substrate to the NPC. The transport of the importin-substrate complex into the nucleus is regulated by the small GTPase Ran/TC4. During the last years more than ten proteins have been discovered which have already been proven or are very likely to be nuclear transport factors of distinct import pathways: members of the importin alpha protein family are very similar and transport in complex with importin beta nuclear localization signal-bearing proteins into the nucleus. Members of the Ran-binding protein family show some weak similarity to importin beta. Sharing a common domain at the amino terminus, they are able to bind RanGTP, a prerequisite for their function as nuclear import or export factors for distinct proteins or RNAs. However, Ran/TC4 seems to play a key regulatory role in all nuclear transport pathways described so far, although the molecular mechanism of the translocation step through the NPC is still unclear.