Key Concepts Of Section 123

Macromolecular Transport Across the Nuclear Envelope

■ The nuclear envelope contains numerous nuclear pore complexes (NPCs), large, complicated structures composed of multiple copies of «50-100 proteins called nucleoporins (see Figure 12-18). FG-nucleoporins, which contain multiple

HIV provirus

NUCLEAR mRNAs

9-kb Q Unspliced

4-kb en-. Singly spliced

Multiply spliced

Transcription, splicing Trnnspon

+Rev

CYTOPLASMIC mRNAs

+Rev

CYTOPLASMIC mRNAs

4-kb en-. Singly spliced

Multiply spliced

Translation

Nucleoplasm

Cytoplasm

Translation

Nucleoplasm

Cytoplasm

▲ FIGURE 12-26 Role of Rev protein in transport of HIV mRNAs from the nucleus to the cytoplasm. The HIV genome, which contains several coding regions, is transcribed into a single 9-kb primary transcript. Several = 4-kb mRNAs result from alternative splicing out of any one of several introns (dashed lines), and several =2-kb mRNAs from splicing out of two or more alternative introns. After transport to the cytoplasm, the various RNA species are translated into different viral proteins. Rev protein, encoded by a 2-kb mRNA, interacts with the Rev-response element (RRE) in the unspliced and singly spliced mRNAs, stimulating their transport to the cytoplasm. [Adapted from B. R. Cullen and M. H. Malim, 1991, Trends Biochem. Sci. 16:346.]

repeats of a short hydrophobic sequence (FG-repeats), line the central transporter channel and play a role in transport of all macromolecules through nuclear pores.

■ Transport of macromolecules larger than =60 kDa through nuclear pores requires the assistance of proteins that interact with both the transported molecule and with FG-repeats of FG-nucleoporins.

■ Proteins imported to or exported from the nucleus contain a specific amino acid sequence that functions as a nuclear-localization signal (NLS) or a nuclear-export signal (NES). Nucleus-restricted proteins contain an NLS but not an NES, whereas proteins that shuttle between the nucleus and cytoplasm contain both signals.

■ Several different types of NES and NLS have been identified. Each type of nuclear-transport signal is thought to interact with a specific receptor protein (exportin or importin) belonging to a family of homologous proteins termed karyopharins.

■ A "cargo" protein bearing an NES or NLS translocates through nuclear pores bound to its cognate receptor protein (karyopharin), which also interacts with FG-nucleoporins. Importins and exportins are thought to diffuse through the channel by binding transiently to different FG-repeats that act like "stepping stones" through the pore. Both transport processes also require participation of Ran, a monomeric G protein that exists in different conformations when bound to GTP or GDP.

■ After a cargo complex reaches its destination (the cytoplasm during export and the nucleus during import), it dissociates, freeing the cargo protein and other components. The latter then are transported through nuclear pores in the reverse direction to participate in transporting additional molecules of cargo protein (see Figures 12-21 and 12-23).

■ The unidirectional nature of protein export and import through nuclear pores results from localization of the Ran guanine nucleotide-exchange factor (GEF) in the nucleus and of Ran GTPase-accelerating protein (GAP) in the cytoplasm. The interaction of import cargo complexes with the Ran-GEF in the nucleoplasm causes dissociation of the complex, releasing the cargo into the nu-cleoplasm (see Figure 12-21). Export cargo complexes dissociate in the cytoplasm when they interact with Ran GAP localized to the NPC cytoplasmic filaments (see Figure 12-23).

■ Most mRNPs are exported from the nucleus by a het-erodimeric mRNA-exporter that interacts with FG-repeats (see Figure 12-24). The direction of transport (nucleus ^ cytoplasm) may result from dissociation of the exporter-mRNP complex in the cytoplasm by an as yet uncharac-terized mechanism that does not depend on Ran.

■ The mRNA-exporter binds to most mRNAs cooperatively with SR proteins bound to exons, to exon-junction complexes that associate with mRNAs following RNA

splicing, and to additional mRNP proteins that remain to be characterized.

■ Pre-mRNAs bound by a spliceosome normally are not exported from the nucleus, assuring that only fully processed, functional mRNAs reach the cytoplasm for translation.

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