16.7:
Regulation of Nuclear Protein Sorting
Nuclear transport is controlled by masking nuclear localization sequences, altering the pore size of the nuclear pore complexes, and secreting precursor proteins.
NLS is masked either by phosphorylation of cargo as observed in the viral transcriptional factor, v-Jun, or by inhibitory proteins that bind the NLS on the cargo as observed in the regulation of NF-kappaB by the I-kappaB. These mechanisms interfere with the NLS recognition process, thereby retaining the cargo in the cytosol or other organelles.
Nuclear pore size is modulated by cytoskeletal proteins to control the size of macromolecules passing through the NPC. As a tight aqueous pore, the NPC expands and contracts to allow selective molecules to squeeze through.
Regulation by precursor proteins is observed in cholesterol metabolism. Sterol response element-binding protein or SREBP, is a precursor of a transcription factor that is present as a transmembrane protein in the ER attached to the SREBP cleavage activation protein or SCAP that is bound to cholesterol.
At low cholesterol concentrations, SCAP changes conformation and the SREBP-SCAP complex gets transported to the Golgi apparatus.
Golgi-resident proteases cleave SREBP's cytosolic domain yielding the active protein. This transcription factor is then imported to the nucleus to activate sterol regulatory DNA sequences.
16.7:
Regulation of Nuclear Protein Sorting
Nuclear protein sorting regulates nucleus composition and gene expression, crucial for determining the fate of a eukaryotic cell. Hence, the entry and exit of molecules across the nuclear envelope is a tightly controlled process. Nuclear protein sorting can be inhibited by one of the following ways: 1) masking cargo signal sequences, 2) modifying the nuclear receptor's affinity for cargo, 3) controlling the nuclear pore size, 4) retaining the cargo during its transit to the cytosol or the nucleus and, 5) secreting precursor proteins.
Masking of sorting signals
Nuclear transport is initiated as nuclear receptors bind to the nuclear localization signals (NLS) or nuclear export signals (NES). To limit the accessibility of the cargo to the nuclear receptors, NLS or NES can be masked by two types of mechanisms. In the first mechanism, the cargo protein undergoes conformational changes through disulfide bond formation or phosphorylation so that it no longer fits into the binding site of the receptor. In the second process, the cargo may bind another molecule, such as DNA, mRNA, or a protein, that interferes with its binding to the receptor.
Modifying nuclear receptors
Phosphorylation of importin alpha by casein kinase II upon binding to NLS of a cargo enhances its importin beta binding affinity and nuclear import. Alternatively, increased levels of importin beta can promote enhanced trafficking of its substrate by outcompeting other nuclear receptors for binding sites on the Nuclear Pore Complexes or NPCs.
Regulating Nuclear pore size
Nuclear pore size also controls the flux of protein transport. Cytoskeletal proteins help constrict or dilate the nuclear pore diameter to restrict cargo entering the nucleus. Alternatively, the extracellular matrix can stretch the nuclear envelope and expand the nuclear pores for cargo import.
Cargo retention
Nuclear trafficking is also restricted when cargo binds to cytosolic factors such as 14-3-3 protein or is tagged for degradation, inhibiting unnecessary transport across the nucleus.
Precursor secretion
Some proteins such as p105 are secreted in the cytoplasm as inactive precursors. Phosphorylation of p105 signals its cleavage to release an active P50 that can be transported to the nucleus.
Suggested Reading
- THOMAS D. SWEITZER et al., Regulation of Nuclear Import and Export, CURRENT TOPICS IN CELLULAR REGULATION, VOLUME 36.
- S. P. Chumakov et al., Organization, and Regulation of Nucleocytoplasmic Transport. ISSN 00268933, Molecular Biology, 2010, Vol. 44, No. 2, pp. 186–201.
- Lucia Boeri et al., Mechanical regulation of nucleocytoplasmic translocation in mesenchymal stem cells: characterization and methods for investigation. Biophysical Reviews (2019) 11:817–831