16.2: Signal Sequences and Sorting Receptors

Signal sequences are short amino acid sequences that guide newly synthesized proteins to their proper location within the cell. Classical signal sequences are fifteen to sixty amino acids long and present at the N-terminus of a polypeptide chain. Each signal sequence has a conserved segment of basic residues towards their N terminus, a hydrophobic core, and a C-terminus rich in polar residues. The C-terminus also contains a signal cleavage site and features a -3 -1 sequence motif. The -3-1 sequence motif contains amino acids with short side chains such as alanine at -1 and uncharged residues at -3 positions, relative to the signal cleavage site (considered position 0).

Cellular organelles contain sorting receptors that recognize the sorting signals and guide the cargo into the correct compartment. Sorting receptors can be soluble such as the nuclear receptors, or membrane-bound, as observed in mitochondria, chloroplast, ER, and peroxisomes. After the proteins are delivered to their proper location, the sorting receptors are recycled back for multiple rounds of protein sorting.

Inside the organelle, signal peptidases cleave the signal sequences of the newly delivered protein at their signal cleavage site. Some signal sequences are present internally within the polypeptide and remain permanently associated without being cleaved off, as found in many nuclear proteins. Furthermore, some signal sequences are rich in hydrophobic amino acid residues that help to anchor transmembrane proteins. Such signal sequences are called signal-anchor sequences. Mutations or removal of signal sequences leads to defective routing of proteins and are associated with physiological conditions such as inherited kidney diseases, autoimmune diseases, cardiovascular diseases, and several metabolic disorders.

Sorting signals are amino acid sequences that guide proteins to their proper location inside the cell. Signal sequences vary in length but are usually 15 to 20 amino acids long, flanking the N-terminal region of a polypeptide chain. 

Some proteins, such as nuclear proteins, can have distant stretches of amino acid residues that come together during protein folding to form three-dimensional arrangements called signal patches.

Sorting signals and signal patches are usually recognized based on the amino acid properties rather than the exact sequence.

Proteins targeted to a particular cell organelle have characteristic features in their signal sequences, such as stretches of hydrophobic residues, positively charged amino acids alternating with hydrophobic residues, and interspersed amino acid residues with hydroxyl-groups.

Signal receptors present on the organelle identify their corresponding signal sequences and transport proteins to the target location.

Once a protein reaches its destination, signal peptidases cleave the signal peptides at their C-terminal signal cleavage site, while the sorting receptors are recycled for catalyzing subsequent rounds of protein sorting.

Modifying the sorting signals can target proteins to a different location. For example, adding the N-terminal signal sequence of ER proteins to cytosolic proteins routes them to the endoplasmic reticulum lumen.