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A secretory protein is any protein, whether it be endocrine or exocrine, which is secreted by a cell. Secretory proteins include many hormones, enzymes, toxins, and antimicrobial peptides. Secretory proteins are synthesized in the endoplasmic reticulum. [1]
The production of a secretory protein starts like any other protein. The mRNA is produced and transported to the cytosol where it interacts with a free cytosolic ribosome. The part that is produced first, the N-terminal, contains a signal sequence consisting of 6 to 12 amino acids with hydrophobic side chains. This sequence is recognised by a cytosolic protein, SRP (Signal Recognition Particle), which stops the translation and aids in the transport of the mRNA-ribosome complex to an SRP receptor found in the membrane of the endoplasmic reticulum. When it arrives at the ER, the signal sequence is transferred to the translocon, a protein-conducting channel in the membrane that allows the newly synthesized polypeptide to be translocated to the ER lumen. The dissociation of SRP from the ribosome restores the translation of the secretory protein. The signal sequence is removed and the translation continues while the produced chain moves through the translocon (cotranslational translocation).
After the production of the protein is completed, it interacts with several other proteins to gain its final state.
After translation, proteins within the ER make sure that the protein is folded correctly. If after a first attempt the folding is unsuccessful, a second folding is attempted. If this fails too the protein is exported to the cytosol and labelled for destruction. Aside from the folding, there is also a sugar chain added to the protein. After these changes, the protein is transported to the Golgi apparatus by a coated vesicle using coating protein COPII.
In the Golgi apparatus, the sugar chains are modified by adding or removing certain sugars. The secretory protein leaves the Golgi apparatus by an uncoated vesicle.
Membrane proteins with functional areas on the cytosolic side of both the vesicle and cell membrane make sure the vesicle associates with the membrane. The vesicle membrane fuses with the cell membrane and so the protein leaves the cell. Some vesicles don't fuse immediately and await a signal before starting the fusing. This is seen in vesicles carrying neurotransmitter in presynaptic cells. This process constitutes an effective cell-cell signaling mechanism via membrane vesicle trafficking from secretory cell to the target cells in human or animal body. Recently, the process has been extended to the host–pathogen interface, wherein, gram negative microbes secrete bacterial outer membrane vesicles containing fully conformed signal proteins and virulence factors via exocytosis of nano-sized vesicles, in order to control host or target cell activities and exploit their environment.
The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum (RER), and smooth endoplasmic reticulum (SER). The endoplasmic reticulum is found in most eukaryotic cells and forms an interconnected network of flattened, membrane-enclosed sacs known as cisternae, and tubular structures in the SER. The membranes of the ER are continuous with the outer nuclear membrane. The endoplasmic reticulum is not found in red blood cells, or spermatozoa.
The endomembrane system is composed of the different membranes (endomembranes) that are suspended in the cytoplasm within a eukaryotic cell. These membranes divide the cell into functional and structural compartments, or organelles. In eukaryotes the organelles of the endomembrane system include: the nuclear membrane, the endoplasmic reticulum, the Golgi apparatus, lysosomes, vesicles, endosomes, and plasma (cell) membrane among others. The system is defined more accurately as the set of membranes that forms a single functional and developmental unit, either being connected directly, or exchanging material through vesicle transport. Importantly, the endomembrane system does not include the membranes of plastids or mitochondria, but might have evolved partially from the actions of the latter.
The Golgi apparatus, also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic cells. Part of the endomembrane system in the cytoplasm, it packages proteins into membrane-bound vesicles inside the cell before the vesicles are sent to their destination. It resides at the intersection of the secretory, lysosomal, and endocytic pathways. It is of particular importance in processing proteins for secretion, containing a set of glycosylation enzymes that attach various sugar monomers to proteins as the proteins move through the apparatus.
Protein targeting or protein sorting is the biological mechanism by which proteins are transported to their appropriate destinations within or outside the cell. Proteins can be targeted to the inner space of an organelle, different intracellular membranes, the plasma membrane, or to the exterior of the cell via secretion. Information contained in the protein itself directs this delivery process. Correct sorting is crucial for the cell; errors or dysfunction in sorting have been linked to multiple diseases.
In cell biology, a vesicle is a structure within or outside a cell, consisting of liquid or cytoplasm enclosed by a lipid bilayer. Vesicles form naturally during the processes of secretion (exocytosis), uptake (endocytosis), and the transport of materials within the plasma membrane. Alternatively, they may be prepared artificially, in which case they are called liposomes. If there is only one phospholipid bilayer, the vesicles are called unilamellar liposomes; otherwise they are called multilamellar liposomes. The membrane enclosing the vesicle is also a lamellar phase, similar to that of the plasma membrane, and intracellular vesicles can fuse with the plasma membrane to release their contents outside the cell. Vesicles can also fuse with other organelles within the cell. A vesicle released from the cell is known as an extracellular vesicle.
Exocytosis is a form of active transport and bulk transport in which a cell transports molecules out of the cell. As an active transport mechanism, exocytosis requires the use of energy to transport material. Exocytosis and its counterpart, endocytosis, are used by all cells because most chemical substances important to them are large polar molecules that cannot pass through the hydrophobic portion of the cell membrane by passive means. Exocytosis is the process by which a large amount of molecules are released; thus it is a form of bulk transport. Exocytosis occurs via secretory portals at the cell plasma membrane called porosomes. Porosomes are permanent cup-shaped lipoprotein structure at the cell plasma membrane, where secretory vesicles transiently dock and fuse to release intra-vesicular contents from the cell.
A transmembrane domain (TMD) is a membrane-spanning protein domain. TMDs may consist of one or several alpha-helices or a transmembrane beta barrel. Because the interior of the lipid bilayer is hydrophobic, the amino acid residues in TMDs are often hydrophobic, although proteins such as membrane pumps and ion channels can contain polar residues. TMDs vary greatly in size and hydrophobicity; they may adopt organelle-specific properties.
The signal recognition particle (SRP) is an abundant, cytosolic, universally conserved ribonucleoprotein that recognizes and targets specific proteins to the endoplasmic reticulum in eukaryotes and the plasma membrane in prokaryotes.
A signal peptide is a short peptide present at the N-terminus of most newly synthesized proteins that are destined toward the secretory pathway. These proteins include those that reside either inside certain organelles, secreted from the cell, or inserted into most cellular membranes. Although most type I membrane-bound proteins have signal peptides, the majority of type II and multi-spanning membrane-bound proteins are targeted to the secretory pathway by their first transmembrane domain, which biochemically resembles a signal sequence except that it is not cleaved. They are a kind of target peptide.
The translocon is a complex of proteins associated with the translocation of polypeptides across membranes. In eukaryotes the term translocon most commonly refers to the complex that transports nascent polypeptides with a targeting signal sequence into the interior space of the endoplasmic reticulum (ER) from the cytosol. This translocation process requires the protein to cross a hydrophobic lipid bilayer. The same complex is also used to integrate nascent proteins into the membrane itself. In prokaryotes, a similar protein complex transports polypeptides across the (inner) plasma membrane or integrates membrane proteins. In either case, the protein complex are formed from Sec proteins, with the heterotrimeric Sec61 being the channel. In prokaryotes, the homologous channel complex is known as SecYEG.
Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classical mechanism of cell secretion is via secretory portals at the plasma membrane called porosomes. Porosomes are permanent cup-shaped lipoprotein structures embedded in the cell membrane, where secretory vesicles transiently dock and fuse to release intra-vesicular contents from the cell.
In cell biology, microsomes are heterogeneous vesicle-like artifacts re-formed from pieces of the endoplasmic reticulum (ER) when eukaryotic cells are broken-up in the laboratory; microsomes are not present in healthy, living cells.
Endoplasm generally refers to the inner, dense part of a cell's cytoplasm. This is opposed to the ectoplasm which is the outer (non-granulated) layer of the cytoplasm, which is typically watery and immediately adjacent to the plasma membrane. The nucleus is separated from the endoplasm by the nuclear envelope. The different makeups/viscosities of the endoplasm and ectoplasm contribute to the amoeba's locomotion through the formation of a pseudopod. However, other types of cells have cytoplasm divided into endo- and ectoplasm. The endoplasm, along with its granules, contains water, nucleic acids, amino acids, carbohydrates, inorganic ions, lipids, enzymes, and other molecular compounds. It is the site of most cellular processes as it houses the organelles that make up the endomembrane system, as well as those that stand alone. The endoplasm is necessary for most metabolic activities, including cell division.
Cell physiology is the biological study of the activities that take place in a cell to keep it alive. The term physiology refers to normal functions in a living organism. Animal cells, plant cells and microorganism cells show similarities in their functions even though they vary in structure.
Signal recognition particle (SRP) receptor, also called the docking protein, is a dimer composed of 2 different subunits that are associated exclusively with the rough ER in mammalian cells. Its main function is to identify the SRP units. SRP is a molecule that helps the ribosome-mRNA-polypeptide complexes to settle down on the membrane of the endoplasmic reticulum.
The unfolded protein response (UPR) is a cellular stress response related to the endoplasmic reticulum (ER) stress. It has been found to be conserved between mammalian species, as well as yeast and worm organisms.
A target peptide is a short peptide chain that directs the transport of a protein to a specific region in the cell, including the nucleus, mitochondria, endoplasmic reticulum (ER), chloroplast, apoplast, peroxisome and plasma membrane. Some target peptides are cleaved from the protein by signal peptidases after the proteins are transported.
Unconventional protein secretion represents a manner in which the proteins are delivered to the surface of plasma membrane or extracellular matrix independent of the endoplasmic reticulum or Golgi apparatus. This includes cytokines and mitogens with crucial function in complex processes such as inflammatory response or tumor-induced angiogenesis. Most of these proteins are involved in processes in higher eukaryotes, however an unconventional export mechanism was found in lower eukaryotes too. Even proteins folded in their correct conformation can pass plasma membrane this way, unlike proteins transported via ER/Golgi pathway. Two types of unconventional protein secretion are these: signal-peptid-containing proteins and cytoplasmatic and nuclear proteins that are missing an ER-signal peptide (1).
David Domingo Sabatini is an Argentine-American cell biologist and the Frederick L. Ehrman Professor Emeritus of Cell Biology in the Department of Cell Biology at New York University School of Medicine, which he chaired from 1972 to 2011. Sabatini's major research interests have been on the mechanisms responsible for the structural complexity of the eukaryotic cell. Throughout his career, Sabatini has been recognized for his efforts in promoting science in Latin America.