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 seque…
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.
View the full transcript and gain access to JoVE Core videos
Q1: What are signal sequences and how long are they typically?
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.
Q2: How do sorting receptors recognize and transport proteins to their destinations?
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.
Q3: What happens to signal sequences after proteins reach their destination?
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.
Q4: What are signal patches and how do they differ from classical signal sequences?
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.
Q5: What characteristic features do signal sequences contain for organellar targeting?
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.
Q6: How can modifying signal sequences change where proteins are targeted?
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.
Q7: What diseases are associated with defective signal sequences?
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.