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 transportedto the nucleus.