Regulation of Protein Function

Much of cell function and its regulation depends upon two basic characteristics of proteins and nucleic acids. We have already seen that DNA and RNA bind with high affinity and great specificity to complementary sequences in other nucleic acid molecules. Similarly, proteins bind to nucleic acids and to other proteins with high specificity. Proteins can also bind specifically to small molecules, including ions and metabolites. This property depends upon the complementarity of shape, charge, and hydrophobicity of interacting surfaces, Van der Waals attractions, and the formation of hydrogen bonds. Such interactions may position a protein at a favorable or unfavorable location with respect to its substrate or regulatory proteins. The second important characteristic of proteins is their ability to assume different conformations when bound to other molecules or when modified covalently by the addition or removal of a small substituent. Such conformational changes may expose, reconfigure, or mask reactive surfaces and thereby profoundly influence the ability of the protein to bind other molecules, to catalyze biochemical reactions, to migrate to or become fixed at a particular cellular locus, and to provide cellular motility.

Protein Phosphorylation

The most important covalent modification of proteins in this regard is the reversible transfer of the bulky, negatively charged terminal phosphate group of ATP (adenosine triphosphate) to ester linkages with hydroxyl groups on serine, threonine, or tyrosine residues. Phosphorylation of proteins is catalyzed by enzymes called protein kinases, which typically contain regulatory as well as catalytic domains. There are hundreds and perhaps thousands of protein kinases that each recognize particular amino acid sequences or motifs in their substrates. Specificity of protein phos-phorylation is conferred by the amino acid sequences of substrates and by the accessibility of substrates to kinases.

Protein phosphorylation was originally thought to result from formation of phosphate esters of serine and threonine residues. When it was later recognized that the hydroxyl group in tyrosine residues may also be phosphorylated, the term tyrosine kinases was coined to distinguish this class of enzymes from the protein kinases that phosphorylate serine and threonine residues. The enzymes that catalyze the dephosphoryla-tion of proteins are known as protein phosphatases and tyrosine phosphatases. These enzymes are less diverse than their kinase counterparts, have a broader range of substrate specificities, and often are constitutively active, but there are important exceptions to these generalizations.

Phosphorylation/dephosphorylation reactions regulate a wide variety of cellular functions. Regulation by this means often involves a cascade of phosphor-ylation reactions, with each kinase serving as substrate for the next kinase in a series. Sequential phosphorylation, and thereby activation, of protein kinases rapidly amplifies a regulatory signal. For example, a single activated protein kinase molecule might catalyze the phosphorylation and hence activation of ten molecules of a second kinase, each of which might then phos-phorylate ten molecules of a third kinase which might then phosphorylate and activate ten molecules of the final effector of the controlled function. In just three steps, the influence of the first activated kinase is amplified 1000-fold. It is important to note that this cascade of reactions can change cellular function within just a few seconds because it modifies the activity of molecules that are already present in the cell. In contrast, changing cell function by modifying gene expression requires many time-consuming steps and usually has a latency of 30 minutes or more.

The consequences of phosphorylation and dephos-phorylation are not limited to conformational changes in the proteins that are the substrates for kinases and phosphatases (Fig. 7). Phosphorylation-related changes in one protein may increase or decrease its ability to bind to other proteins, which may thereby become activated or inhibited. In addition, the phosphate ester of tyrosine residues along with the adjacent amino acids in a loop of protein may provide a specific docking site to which a complementary peptide sequence in another protein may bind. These interactions are important in regulation of cell function by extracellular agents and in forming protein complexes required to carry out some particular cellular task. One important task that may be regulated in this way is control of gene expression through modification of the activity of nuclear regulatory proteins.

Partial Hydrolysis

Another means of regulating protein function is through proteolytic cleavage. Clipping off a segment of protein can expose a reactive surface on the remaining protein or may simply permit a conformational change to occur. Additionally, the activities of some proteins may be restrained by the presence of other proteins that

FIGURE 7 Phosphorylation of proteins produces changes in configuration that result in (A) increasing or umasking of catalytic activity or (B) directly enabling proteins to interact. These phenomena might also occur as a result of dephosphorylation. In (C), phosphory-lation of one protein provided a docking site for a second protein which permitted interaction with a third protein.

FIGURE 7 Phosphorylation of proteins produces changes in configuration that result in (A) increasing or umasking of catalytic activity or (B) directly enabling proteins to interact. These phenomena might also occur as a result of dephosphorylation. In (C), phosphory-lation of one protein provided a docking site for a second protein which permitted interaction with a third protein.

act as inhibitors. Proteolytic destruction or inactivation of such an inhibitor allows expression of the activity. Alternatively, the activities of some proteins are limited by the binding of a portion of their peptide chains to a particular cellular locus which restricts their access to substrate. Cleaving a peptide bond in the portion of the protein that anchors it frees the rest of the protein to diffuse to its substrate.

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