Proteins are the major building blocks of life. Eukaryotic cells synthesize proteins for thousands of different functions. Some examples:
- to build the components of the cytosol (e.g. microtubules, glycolytic enzymes);
- to build the receptors and other molecules exposed at the surface of the cell embedded in the plasma membrane;
- to supply some of the components of the mitochondria and (in plant cells) chloroplasts;
- proteins secreted from the cell to supply the needs of other cells and tissues (e.g. collagens to support cells, hormones to signal them).
All proteins are synthesized by ribosomes using the information encoded in molecules of messenger RNA (mRNA). This process is called translation and is described in Gene Translation: RNA -> Protein. Our task here is to explore the ways that these proteins are delivered to their proper destinations.
The various destinations for proteins occur in two major sets:
So the first decision that must be made as a ribosome begins to translate a mRNA into a polypeptide is whether to remain free in the cytosol or to bind to the ER.
The decision to enter the ER is dictated by the presence of a signal sequence on the growing polypeptide.
- one set for those proteins synthesized by ribosomes that remain suspended in the cytosol, and
- a second set for proteins synthesized by ribosomes that are attached to the membranes of the endoplasmic reticulum (ER) forming "rough endoplasmic reticulum" (RER). This electron micrograph (courtesy of Keith Porter) shows the RER in a bat pancreas cell. The clearer areas are the lumens.
The signal sequence in many proteins consists of the first portion of the elongating polypeptide chain (so the signal sequence occurs at the amino terminal of the polypeptide). Typical signal sequences contain about 15 amino acids. The precise amino acid sequence varies surprisingly from one protein to the next, but all signal sequences include many hydrophobic amino acids.
|The 1999 Nobel Prize in Physiology or Medicine was awarded on October 11, 1999 to Dr. Günter Blobel for his discovery of the signal sequence and other intrinsic signals that enable proteins to reach their proper destinations.|
If a signal sequence is present,
- translation ceases after it has been synthesized.
- The signal sequence is recognized by and is bound by a signal recognition particle (SRP).
- The complex of ribosome with its nascent polypeptide and the SRP binds to a receptor on the surface (facing the cytosol) of the ER.
- The SRP leaves and translation recommences.
- The growing polypeptide chain is extruded through a pore in the ER membrane and into the lumen of the ER.
- The signal sequence is usually clipped off the polypeptide unless the polypeptide is to be retained as an integral membrane protein.
- Other proteins, called molecular chaperones, present in the lumen of the ER, bind the growing polypeptide chain and assist it to fold into its correct tertiary structure.
- Sugar residues may be added to the protein. The process is called glycosylation and often is essential for proper folding of the final product, a glycoprotein.
Destinations of proteins synthesized within the ER
Proteins synthesized within the ER are transported to the Golgi apparatus. Portions of the ER are pinched off, forming transport vesicles. These carry their load of proteins to the Golgi apparatus. The membrane of the transport vesicle fuses with the membrane of the Golgi apparatus, merging their contents. Further steps of glycosylation may occur within the Golgi apparatus. The exact pattern of glycosylation determines the final destination of the proteins. There are two options.
- proteins glycosylated with residues of mannose-6-phosphate will leave the Golgi in transport vesicles that eventually fuse with lysosomes (path 2 in the figure).
- proteins that do not receive this marker, leave in transport vesicles that eventually fuse with the plasma membrane (path 1 in the figure). These are:
- integral membrane proteins that become exposed at the surface of the cell (forming receptors and the like) and
- proteins in solution within the transport vesicle. These are discharged from the cell. This secretory process is called exocytosis.
The Signal Recognition Particle (SRP)
The signal recognition particle in mammalian cells is made from:
It contains binding sites for:
- a single small (7S) molecule of RNA
- six different molecules of protein
[Return to signal sequence]
Ribosomes synthesizing a protein without a signal sequence do not bind to the ER and continue synthesis until the polypeptide is completed. Chaperones are also present in the cytosol that help the protein assume its final three-dimensional configuration. Some of the important destinations for these proteins are:
- the signal sequence
- the ribosome, and
- an SRP receptor, also called the docking protein, on the cytosol face of the membranes of the ER.
15 February 2020