3.3 - The secretory pathway

Making a protein for secretion

A cell must send a protein to a suitable destination as well as assemble the correct amino acid sequence.

For example, pancreatic cells secrete amylase into ducts that carry it to the small intestine, where it helps digest starch. The intestinal contents are outside the pancreatic cells even though they are within the body. “Extracellular” describes the enzyme's place of action relative to a cell, not whether it is outside the organism.

Recall that translation joins amino acids into a polypeptide according to the codons on mRNA. The ribosome catalyses peptide-bond formation; tRNA brings the amino acids. For a protein following this secretory route, a targeting signal in the growing chain directs synthesis to the rough endoplasmic reticulum (rER). Detailed targeting machinery is not needed to follow the route.

The rER is a network of membrane-bound sacs called cisternae. Ribosomes attached to its cytoplasmic surface give it a rough appearance. The space enclosed by an ER membrane is its lumen. As translation continues at an attached ribosome, the growing polypeptide enters the lumen through a protein channel in the ER membrane. The ribosome and mRNA remain on the cytoplasmic side; they do not travel inside the ER with the protein.

Inside the rER, the polypeptide folds into a three-dimensional structure and may undergo initial processing. Folding matters because an enzyme needs an appropriately shaped active site. The rER therefore connects protein synthesis with preparation and transport of proteins for secretion. A ribosome makes the polypeptide; the ER membrane is not itself the machinery that joins amino acids.

Many proteins that function in the cytosol are made on free ribosomes and remain there. Not every cellular protein passes through the rER and Golgi, and attached and free ribosomes are not two different kinds of protein-making machine.

Transport and processing at the Golgi

A newly made secretory protein moves between separate organelles while remaining enclosed by membranes.

A transport vesicle is a small membrane-bound compartment carrying material between locations. At an exit region of the ER, membrane buds out around protein cargo and pinches off to form a vesicle. The secreted enzyme is in the vesicle's interior, derived from the ER lumen; it is not loose in the surrounding cytosol. Ribosomes are not packaged with it.

The vesicle travels to the Golgi apparatus, a stack of flattened membrane-bound cisternae. Its membrane fuses with the receiving side of the Golgi, allowing the cargo to enter a Golgi lumen. The receiving side is called the cis face; proteins progress towards the trans face, from which outgoing cargo is sorted. The Golgi is a distinct organelle, not a long ribosome-covered extension of the rER.

Enzymes within the Golgi can modify proteins as they progress through the stack. For example, carbohydrate groups attached to some proteins can be altered, producing or modifying glycoproteins. Not every secreted enzyme receives the same modification. Modification changes an existing protein; it does not mean that Golgi ribosomes translate a second amino acid chain. The Golgi does not have attached ribosomes carrying out translation.

The Golgi also sorts proteins into vesicles for their destinations. Cargo for release outside the cell is packaged into secretory vesicles that bud from the exit region. Other Golgi cargo can have other destinations, such as lysosomes; arrival at the Golgi alone does not mean that a protein must be secreted.

This division of labour explains why a cell that exports large amounts of protein can have extensive rER and a well-developed Golgi. More rER provides more membrane-associated synthesis and processing capacity, while the Golgi processes and sorts that output. A large number of ribosomes alone would not supply the whole delivery route.

Releasing the enzyme by exocytosis

A secretory vesicle delivers its soluble protein cargo to the cell surface without requiring that protein to diffuse through an intact lipid bilayer.