Proteins are fundamental molecules in all living cells, performing diverse functions from structural support to catalyzing biochemical reactions. For these tasks to be effective, each protein must reach its precise location within the cell or be secreted. The accurate delivery of proteins to their correct destinations is a sophisticated and tightly regulated process. This precise targeting ensures that cellular processes proceed efficiently, maintaining the cell’s overall health and function.
The Cell’s Internal Address System
Cells employ an intrinsic “address system” to guide proteins to their specific cellular locations. This system relies on specific amino acid sequences, known as signal sequences or targeting signals, embedded within the protein itself. These sequences function much like a molecular zip code, containing the necessary information for the cell’s machinery to recognize and direct the protein. Signal sequences are typically short stretches of amino acids, often found at the protein’s beginning (N-terminus), but can also be internal or at the end (C-terminus).
Specialized cellular components, such as receptor proteins, recognize these signal sequences. Upon recognition, these components bind to the protein, initiating transport. This recognition step ensures that only proteins designated for a particular destination are routed there, preventing mislocalization. The precise binding and interaction between the signal sequence and its corresponding cellular machinery are important for accurate protein sorting within the cellular environment.
Transport via the Endoplasmic Reticulum and Secretory Pathway
Many proteins destined for secretion, membrane insertion, or delivery to organelles like lysosomes first enter the endoplasmic reticulum (ER). This entry is often co-translational, meaning protein synthesis and translocation into the ER occur simultaneously. As a protein’s signal sequence emerges from the ribosome, it is recognized by the signal recognition particle (SRP). SRP binds to this sequence and the ribosome, pausing synthesis and directing the complex to the ER membrane.
Upon reaching the ER, the SRP-ribosome complex interacts with an SRP receptor on the ER membrane. This facilitates transfer of the ribosome and nascent polypeptide chain to a protein-conducting channel, the translocon. Protein synthesis then resumes, and the growing chain is threaded into the ER lumen or integrated into the ER membrane. Within the ER lumen, proteins undergo modifications, including proper folding with the help of chaperone proteins and the addition of sugar chains (glycosylation).
Following processing in the ER, proteins move to the Golgi apparatus, a central sorting station, via transport vesicles. These vesicles bud off from the ER, transport their cargo, and fuse with the Golgi membrane, releasing proteins into its lumen. As proteins traverse the different compartments of the Golgi, they undergo further processing, modification, and sorting. The Golgi acts as a distribution center, packaging proteins into new vesicles targeted to various destinations, such as the plasma membrane for secretion or lysosomes.
Direct Delivery to Specific Organelles
Not all proteins pass through the ER-Golgi pathway; some are synthesized entirely in the cytoplasm and delivered directly to their target organelles. This process, termed post-translational import, occurs for proteins destined for the nucleus, mitochondria, and peroxisomes. Each of these organelles possesses unique targeting signals and import machinery tailored to its specific requirements.
Proteins destined for the nucleus contain nuclear localization signals (NLSs), typically short sequences rich in basic amino acids. These NLSs are recognized by soluble transport receptor proteins called importins in the cytoplasm. The importin-protein complex then binds to the nuclear pore complex (NPC), a large protein structure spanning the nuclear envelope, and is actively transported through it. Once inside the nucleus, the protein is released, a process regulated by the small GTPase Ran, which helps dissociate the importin-cargo complex and recycle importins back to the cytoplasm.
Mitochondria import most of their proteins from the cytosol, even though they possess their own DNA. Many mitochondrial proteins have an N-terminal presequence that acts as a targeting signal. These proteins are recognized by receptor complexes on the mitochondrial outer membrane, such as the TOM complex. After passing through TOM, proteins are guided through various TIM complexes to reach specific sub-compartments within the mitochondria, such as the matrix or inner membrane.
Peroxisomes also receive their proteins directly from the cytoplasm, and can import proteins that are already folded. Peroxisomal matrix proteins typically contain specific peroxisomal targeting signals (PTS), with the most common being PTS1. These signals are recognized by a soluble receptor protein, Pex5, in the cytosol, which then escorts the protein to the peroxisomal membrane. The Pex5-cargo complex interacts with specific Pex proteins on the peroxisome, facilitating cargo translocation into the peroxisomal matrix, after which the receptor is recycled.