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Post-translational Control

Post-translational Control

Post-translational control can be defined as the mechanisms by which protein structure can be altered after translation. Proteins are polymers of amino acids, and there are twenty different amino acids. Both the order and identity of these amino acids are important for the role that the protein plays in the cell. In some cases, the chemical identity of these amino acids is changed after translation. Alternatively, the sequence or number of the amino acids in a protein can be altered. These changes can alter the structure or function of the protein, or they can target it for destruction.

Alterations of Amino Acids

Post-translational control of protein function or structure can be accomplished by chemical alteration of an amino acid side chain or by modification of the ends of the protein backbone. While there are many diverse chemical modifications of amino acids, three common examples are phosphorylation, glycosylation, and ubiquitination.

Phosphorylation involves the addition of phosphate to an amino acid side chain, usually to the side chain hydroxyl (-OH) of serine, threonine, or tyrosine. This modification results from the action of a protein known as a kinase and uses ATP as the source of phosphate. The phosphate can be removed by another enzyme, a phosphatase. Phosphorylation can alter protein function and is relevant in cellular signaling pathways. Aberrant phosphorylation can lead to disruption of the cell cycle and the induction of cancer.

Glycosylation involves the addition of one or more sugar monomers to the side chains of amino acids, either during or after translation, to make a glycoprotein . Sugars are attached either to the side-chain nitrogen of the amino acid asparagine or to the hydroxyl of the amino acids serine or threonine. The structure of these carbohydrates can be complex and variable and often does not affect the function of proteins directly. However, glycosylation can affect the protein's solubility, its targeting to a particular part of the cell, its folding into a three-dimensional structure, its lifetime before it is degraded, and its interaction with other proteins.

The addition of ubiquitin (a protein composed of seventy-six amino acids) to another protein can render the target protein susceptible to degradation by the 26S proteosome, which is a large protease (a protein that cleaves other proteins). Ubiquitin is ubiquitous in the cell (hence its name) and varies little between organisms as diverse as yeast and humans. It is attached via the side chain of the amino acid lysine, and often additional ubiquitin proteins are added to the first to make a chain.

Alteration of the Polypeptide Backbone

Control of protein function by post-translational modification may also occur by altering the order of the amino acids in the protein backbone. These modifications may be promoted by other proteins or they may be self-directed.

Certain proteins are synthesized as larger precursor proteins and are activated by cleavage of their peptide backbone by proteases. Many of these large protein precursors, called zymogens or proproteins, are synthesized with an N-terminal signal sequence that instructs the cell to export the protein. (Proteins have an amino group at one end and a carboxyl group at the other. The amino-group end is called the N-terminus, the carboxyl end is called the C-terminus.) The N-terminal signal sequences are then cleaved, but the exported protein may still be inactive until cleaved again by another protease. Proteins activated by this mechanism include digestive proteases such as trypsin, the activity of which must be controlled before export by the cell. Serum albumin is also processed in this manner, as are the peptide hormones insulin, vasopressin, and oxytocin. Post-translational cleavage is also responsible for controlling the process of blood clotting.

Inteins

Proteins can also direct the rearrangement of their own polypeptide backbones. For instance, proteins called inteins facilitate a process known as protein splicing. Inteins interrupt the amino acid sequence, and probably the function, of other proteins. Examples include an intein in yeast that interrupts an ATPase, one in a mycobacteria that interrupts the RecA protein (which is involved in DNA repair and recombination), and one in a pyrococcus species that interrupts a DNA polymerase.

Inteins promote their own excision from their target protein as well as the ligation of the flanking protein segments, which are called exteins. It is possible that some inteins play a role in regulating gene expression, but it is also possible that they are vestiges of ancient control mechanisms or simply molecular parasites.

Inteins are analogous to introns in an RNA transcript. Introns interrupt a gene in DNA. The introns are excised after transcription from the surrounding RNA sequences. These flanking sequences, called exons, are then spliced together. Unlike protein splicing, RNA splicing is usually aided by other proteins and RNA molecules.

While it is unclear if protein splicing has a regulatory role, a class of proteins evolutionarily related to inteins, the hedgehog proteins, are involved in embryonic patterning and segmentation. Hedgehog proteins promote their own internal cleavage, coupled to the addition of cholesterol to the C-terminal end of the N-terminal fragment, which is probably important for anchoring the hedgehog protein in the cell membrane.

see also RNA Processing; Signal Transduction; Transcription.

Kenneth V. Mills

Bibliography

Creighton, Thomas E. Proteins: Structure and Molecular Properties. New York: W. H.Freeman, 1993.

Neurath, Hans, and Kenneth A. Walsh. "Role of Proteolytic Enzymes in Biological Regulation (A Review)." Proceedings of the National Academy of Sciences (USA) 73 (1976): 3825-3832.

Paulus, Henry. "Protein Splicing and Related Forms of Protein Autoprocessing." Annual Review of Biochemistry 69 (2000): 447-496.

Schwartz, Alan L., and Aaron Ciechanover. "The Ubiquitin-Proteasome Pathway and Pathogenesis of Human Diseases." Annual Review of Medicine 50 (1999): 57-74.

Stryer, Lubert. Biochemistry. New York: W. H. Freeman, 1995.

Uy, Rosa, and Finn Wold. "Posttranslational Covalent Modification of Proteins." Science 198 (1977): 890-896.

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