Nuclear localization signals (NLS) facilitate the transport of proteins into the nucleus.
Bipartite binding mode of the mammalian NLS is achieved via two basic clusters of the NLS, which are connected by a poorly
ordered linker (10-12 residues). Electron density maps evidence the peptide binding simultaneously in alternative modes
(registers): in the vicinity of the P5, P1 (alternative rotamers), P6 (staggering of KKKK
cluster one position C-terminally) and P-P34 (staggering of KR cluster two positions C-terminally) positions.
The poorly ordered linker (10-12 residues) is tolerant to mutations.
The fuzzy linker modulates specificities of different importin - α isoforms for different cargo proteins.
The fuzzy linker may account for diverse NLS binding by the same receptor.