This blog post explores the intricate mechanism by which proteins navigate the complex internal structures of cells, using signal sequences as guides to reach the location where they must perform their function.
When viewed under a microscope, a cell appears like a small droplet. However, its interior is actually divided into multiple compartments by membranes composed of lipid components. Just as items would become jumbled and difficult to find without drawers inside a cabinet, the absence of compartments within a cell would cause its contents—especially proteins—to mix indiscriminately, potentially disrupting cellular function. Therefore, each protein must be precisely transported to its required location within the cell—whether to organelles, the cytoplasm, specific parts of the cell, or the cell membrane—according to its specific function.
Proteins secreted outside the cell act like hormones, transmitting signals to other cells. Additionally, proteins anchored to the cell membrane function as receptors, receiving signals from outside the cell like antennas, or as channels, facilitating the entry of substances into the cell. Conversely, proteins transported to intracellular organelles or those present in the cytoplasm primarily act as catalysts, accelerating biochemical reactions occurring within those organelles or the cytoplasm.
Proteins are synthesized in ribosomes according to the information in mRNA. Ribosomes exist independently within the cytoplasm filling the cell interior. When they bind to mRNA and protein synthesis begins, they either continue protein synthesis within the cytoplasm or move to the endoplasmic reticulum, an organelle inside the cell, where they attach to its surface and continue protein synthesis. The reason ribosomes perform protein synthesis at these two distinct locations within the cell is that the synthesized proteins must be delivered to different destinations according to their function. Proteins completed by ribosomes existing independently in the cytoplasm primarily move to intracellular organelles like the cytoplasm, cell nucleus, or mitochondria to perform their functions. Conversely, proteins synthesized by ribosomes on the endoplasmic reticulum are secreted outside the cell, located in the cell membrane, or transported to intracellular organelles such as the endoplasmic reticulum, Golgi apparatus, or lysosomes. The endoplasmic reticulum, Golgi apparatus, and lysosomes are all physically connected, facilitating the movement of proteins synthesized on ribosomes on the endoplasmic reticulum. Furthermore, proteins that are anchored to the cell membrane or secreted by passing through the cell membrane are transported towards the cell membrane, enclosed in vesicles, after passing through the endoplasmic reticulum and Golgi apparatus.
Proteins completed on ribosomes atop the endoplasmic reticulum may also move to the Golgi apparatus, another intracellular organelle located in close proximity to the endoplasmic reticulum. There, they undergo additional modifications before proceeding to their final destination. This post-synthesis modification process involves attaching carbohydrate or lipid molecules to the protein formed by linked amino acids, conferring unique functions that amino acids alone cannot achieve. Some enzymes functioning in the endoplasmic reticulum are proteins that complete synthesis on ribosomes atop the endoplasmic reticulum, move to the Golgi apparatus for modification, and then return to the endoplasmic reticulum.
How exactly do proteins find their intended location within the cell? This is explained by the signal sequence theory. Certain proteins possess a signal sequence, a short amino acid sequence indicating their intended intracellular destination. For example, the KDEL signal sequence is found on proteins synthesized on ribosomes atop the endoplasmic reticulum, which then undergo additional modifications in the Golgi apparatus before returning to the endoplasmic reticulum. Similarly, the NLS is a signal sequence found in proteins synthesized on ribosomes independent of the cytoplasm and destined for the cell nucleus. Conversely, the NES is a signal sequence found in proteins that originate in the cell nucleus and are destined for the cytoplasm. Additionally, the MTS exists as a signal sequence for transporting proteins synthesized on ribosomes independent of the cytoplasm to the mitochondria.
Several experiments were conducted to prove this signal sequence theory. Proteins artificially fused with the KDEL signal sequence were observed to localize to the endoplasmic reticulum instead of their intended destination, leading to the conclusion that KDEL is a signal sequence determining protein transport to the endoplasmic reticulum. Additionally, experiments were conducted to determine whether certain proteins synthesized by ribosomes attached to the endoplasmic reticulum are secreted outside the cell because they possess a specific signal sequence, or whether they are secreted because they lack any signal sequence. The results concluded that this varies depending on the cell type. Furthermore, experiments were conducted to determine how proteins lacking a signal sequence for transport to a specific intracellular location could still reach that destination. The results concluded that such proteins could be transported to the specific location designated by the signal sequence through binding to proteins possessing the signal sequence for that particular destination.
Thus, the precise localization and transport of proteins are central to maintaining cellular function, and signal sequence theory has established itself as a crucial theoretical foundation for explaining this intricate transport system.
