8.9: Regulating protein activity, concentrations, and stability (half-life)

Proteins act through their interactions with other molecules. Catalytic proteins (enzymes) interact with substrate molecules; these interactions lower the activation energy of the reaction's rate limiting step, resulting in an increase in the overall reaction rate. At the same time, cells and organisms are not static. They must regulate which proteins they produce, the final concentrations of those proteins, how active those proteins are, and where those proteins are located. It is primarily by altering proteins that in turn influence gene expression, that cells and organisms adapt to changes in their environment.

A protein's activity can be regulated in a number of ways. The first and most obvious is to control the total number of protein molecules present within the system. Let us assume that once synthesized a protein is fully active. With this assumption, the total concentration of a protein, and the total protein activity in a system [P_sys] is proportional to the rate of that protein’s synthesis (dSynthesis/dt) minus the rate of that protein’s degradation (dDegradation/dt), with dt indicating per unit time. The combination of these two processes, synthesis and degradation, determines the protein’s concentration in the cell. Both the rate of protein’s synthesis and degradation can be regulated. These processes can influence the rate at which a cell (or organism) can respond to various perturbations.

The degradation of proteins is mediated by a special class of enzymes known as proteases. Proteases cleave peptide bonds via hydrolysis (adding water) reactions. Proteases that cleave a polypeptide chain internally are known as endoproteases - they generate two polypeptides. Those that hydrolyze polypeptides from one end or the other, generally release one or two amino acids at a time, and are known as exoproteases. Proteases can also recognize and remove specific parts of a protein in order to activate or inactivate it, or to control where it is found in a cell. For example, nuclear proteins become localized to or excluded from the nucleus because they contain a NLS or an NES (see above). For these sequences to work they have to interact with the transport machinery associated with nuclear pores; but a protein may be folded so that its NLS/NES sequences are hidden, that is not visible on its surface. Changes in a protein’s structure can reveal or hide such sequences, thereby altering the protein’s distribution within the cell and therefore its activity. As an example, a transcription factor located in the cytoplasm is, in terms of its effects on gene expression, inactive; it becomes active if it enters the nucleus. Similarly, many proteins are originally synthesized in a longer and inactive "pro-form". When the pro-peptide is removed, cut away by an endoprotease, the processed protein becomes active. Proteolytic processing itself can be regulated.

As with all molecular level processes, the final breakdown of a protein is stochastic, based on collisions. Degradation can be regulated, signals within or added to a molecule can influence whether a collision with a degrading complex will be productive, that is, whether the molecule will be broken down. Protein degradation is particularly important for controlling the levels of “regulated” proteins, whose concentration within the cell may lead to unwanted effects. The rate of molecular degradation can be regulated, generally through the presence or addition of a signal that serves to influence the outcome of collisions with the degradative machinery (→). Degradation is an active and highly regulated process, involving ATP hydrolysis and multi-subunit complexes. One of these, involved in protein degradation, is known as the proteosome. The proteosome degrades the polypeptide into small peptides and amino acids that can be reused. As a mechanism for regulating protein activity, however, degradation has a serious drawback, it is irreversible.

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