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Signal sequences are amino acid sequences that guide proteins to their proper location inside the cell. They are usually 15 to 20 amino acids long and flank the N-terminal region of a polypeptide chain. Classical signal sequences can range from 15 to 60 amino acids and contain a conserved segment of basic residues, a hydrophobic core, and a C-terminus rich in polar residues.

Sorting receptors present on organelles identify corresponding signal sequences based on amino acid properties rather than exact sequence. These receptors can be soluble, like nuclear receptors, or membrane-bound, as found in mitochondria and chloroplasts. After delivering proteins to their target location, sorting receptors are recycled for multiple rounds of protein sorting.

Signal peptidases cleave signal peptides at their C-terminal signal cleavage site once proteins reach their destination. However, some signal sequences remain permanently associated with proteins without being cleaved, particularly in nuclear proteins and transmembrane proteins. The signal cleavage site features a -3-1 sequence motif containing amino acids with short side chains.

Signal patches are three-dimensional arrangements formed by distant stretches of amino acid residues that come together during protein folding, particularly in nuclear proteins. Unlike classical N-terminal signal sequences, signal patches are internal and recognized based on their spatial structure rather than linear sequence. They guide proteins to their proper organellar location through their distinctive three-dimensional properties.

Signal sequences contain characteristic features such as stretches of hydrophobic residues, positively charged amino acids alternating with hydrophobic residues, and interspersed amino acid residues with hydroxyl-groups. These properties allow sorting receptors to recognize and bind specific signal sequences. Signal-anchor sequences, which are rich in hydrophobic amino acids, help anchor transmembrane proteins within organellar membranes.

Modifying or adding signal sequences can redirect proteins to different cellular locations. For example, adding the N-terminal signal sequence of endoplasmic reticulum proteins to cytosolic proteins routes them to the ER lumen instead of their original destination. This demonstrates that signal sequences are the primary determinants of protein localization.

Mutations or removal of signal sequences leads to defective protein routing and is associated with inherited kidney diseases, autoimmune diseases, cardiovascular diseases, and several metabolic disorders. Proper signal sequence recognition and protein sorting are essential for maintaining cellular function and preventing pathological conditions.