Key Concepts of Section 3.4

• Proteins may be regulated at the level of protein synthesis, protein degradation, or the intrinsic activity of proteins through noncovalent or covalent interactions.

• The life span of intracellular proteins is largely determined by their susceptibility to proteolytic degradation.

• Many proteins are marked for destruction with a polyubiquitin tag by ubiquitin ligases and then degraded within proteasomes, large cylindrical complexes with multiple protease active sites in their interior chambers (see Figure 3-31).

• Ubiquitinylation of proteins is reversible due to the activity of deubiquitinylating enzymes.

• In allostery, the noncovalent binding of one ligand molecule, the allosteric effector, induces a conformational change that alters a protein’s activity or affinity for other ligands. The allosteric effector can be identical in structure to or different from the other ligands, whose binding it affects. The allosteric effector can be an activator or an inhibitor.

• In multimeric proteins, such as hemoglobin, that bind multiple identical ligand molecules (e.g., oxygen), the binding of one ligand molecule may increase or decrease the protein’s affinity for subsequent ligand molecules. This type of allostery is known as cooperativity (see Figure 3-32).

• Several allosteric mechanisms act as switches, turning protein activity on and off in a reversible fashion.

• Two classes of intracellular switch proteins regulate a wide variety of cellular processes: (1) Ca²⁺-binding proteins (e.g., calmodulin) and (2) members of the GTPase superfamily (e.g., Ras), which cycle between active GTP-bound and inactive GDP-bound forms (see Figure 3-34). GTPases participate in complex regulatory networks that include proteins (GAP, GEF, GDI) that regulate the cycling of the GTPase between its active and inactive forms.

• The phosphorylation and dephosphorylation of hydroxyl groups on serine, threonine, or tyrosine side chains by protein kinases and phosphatases provide reversible on/off regulation of numerous proteins (see Figure 3-35).

• Variations in the nature of the covalent attachment of ubiquitin to proteins (mono-, multi-, and polyubiquitinylation involving a variety of linkages between the ubiquitin monomers) are involved in a wide variety of cellular functions other than proteasome-mediated degradation, such as changes in the location or activity of proteins (see Figure 3-36).

• Many types of covalent and noncovalent regulation are reversible, but some forms of regulation, such as proteolytic cleavage, are irreversible.

• Higher-order regulation includes the intracellular location, or compartmentation, of proteins.