Protein Targeting and Degradation:- Signal Sequences for Nuclear Transport Are Not Cleaved
Molecular communication between the nucleus and the cytosol requires the movement of macromolecules through nuclear pores. RNA molecules synthesized in the nucleus are exported to the cytosol. Ribosomal pro teins synthesized on cytosolic ribosomes are imported into the nucleus and assembled into 60S and 40S ribo somal subunits in the nucleolus; completed subunits are then exported back to the cytosol. A variety of nuclear proteins (RNA and DNA polymerases, histones, topo isomerases, proteins that regulate gene expression, and so forth) are synthesized in the cytosol and imported into the nucleus. This traffic is modulated by a complex system of molecular signals and transport proteins that is gradually being elucidated. In most multicellular eukaryotes, the nuclear enve lope breaks down at each cell division, and once divi sion is completed and the nuclear envelope reestab lished, the dispersed nuclear proteins must be reimported. To allow this repeated nuclear importation, the signal sequence that targets a protein to the nucleus—the nuclear localization sequence, NLS—is not removed after the protein arrives at its destination. An NLS, unlike other signal sequences, may be located almost anywhere along the primary sequence of the protein. NLSs can vary considerably, but many consist of four to eight amino acid residues and include several consecutive basic (Arg or Lys) residues. Nuclear importation is mediated by a number of proteins that cycle between the cytosol and the nucleus , including importin α and β and a small GTPase known as Ran. A heterodimer of importin α and β functions as a soluble receptor for proteins targeted to the nucleus, with the subunit binding NLS-bearing
proteins in the cytosol. The complex of the NLS bearing protein and the importin docks at a nuclear pore and is translocated through the pore by an energy dependent mechanism that requires the Ran GTPase. The two importin subunits separate during the translocation, and the NLS-bearing protein dissociates from importin α inside the nucleus. Importin and are then exported from the nucleus to repeat the process. How importin α remains dissociated from the many NLS bearing proteins inside the nucleus is not yet clear.
FIGURE 27–36 Phosphorylation of mannose residues on lysosome-targeted enzymes. N-Acetylglucosamine phosphotransferase recognizes some as yet unidentified structural feature of hydrolases destined for lysosomes.
