The nuclear localization signal (NLS) is typically enriched in:
Classical nuclear localization signals are defined chemically by clustering of positively charged side chains within short peptide stretch. Monopartite type contains four to five consecutive basic residues such as Lys-Lys-Lys-Arg-Lys originally identified in SV40 large T antigen, while bipartite type features two basic clusters separated by ten to twelve residues, exemplified by nucleoplasmin KRPAATKKAGQAKKKK and many transcription factors. Arginine guanidinium and lysine ammonium groups provide both electrostatic attraction and hydrogen bonding to acidic and aromatic residues lining major and minor grooves of importin-alpha armadillo repeats. Systematic alanine scanning shows replacement of basic residues abolishes nuclear accumulation, whereas fusion of polybasic sequence confers constitutive nuclear targeting to cytosolic reporters like pyruvate kinase. Leucine-rich sequences define export signals interacting with CRM1, tyrosine-based YXXΦ motifs mediate clathrin endocytosis, methionine-rich regions mark SRP binding, so enrichment in arginine and lysine uniquely marks NLS distinguishing import information, with phosphorylation adjacent modulating affinity during cell cycle, stress and signal transduction to control nuclear availability of regulators and transcription factors. Additional coordination with cellular stress pathways ensures fidelity, prevents aggregation, and links trafficking to growth control and proteostasis maintenance across diverse cell types and developmental stages.
Ref: Lodish et al., Molecular Cell Biology, 9th ed., Chapter 13: Basic Residues in Classical NLS.