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VVfeaÎL nnd Strong fonds Determine Macromolecular Structure

FIGURE 5-26 The allasreric modification of aspartate transcarbamoylase (ATCase) by CTP.

aliosteric active sites tntiibitor site aliosteric active sites tntiibitor site

I | catalytic polypeptide substrate m regulatory polypeptide J CTP (inhibitor)

Phosphorylation as Effector: Cdk Activation by CAK As we have just seen, Cclks are activated by binding eye ¡ins. Full activation of Cdk requires a second allosteric change in that enzyme, mediated by phosphorylation. This phosphorylation takes place on a threonine residue within the T loop mentioned above. This modification leads to further

PSTAIRE helix

T loop

PSTAIRE helix

T loop

FIGURE 5-27 Cyclin-induced conformational changes in Cdk. (a)

The monomerc kinase structure, shown in turquoise, ts inactive. The position ot the PSTAIRE helix holds a critical residue otu of the catalytic center, where ATP fs located, and the T loop blocks access to the protein substrate {not shown), (b) The structure shows the repositioning of the helix upon binding of cydin (shown in purple) and the removal of the loop from the opening of the catalytic center This complex is partially active, (c) Upon phosphorylation of the T loop (shown in red), the Cdk-cydin complex becomcs fuliy active. (Schulze-Gahmen U., De Bondt H.L, and Kim S.H. \996. J Med Chem 39: 4540; Jeffrey P.D., Russo AA, Polyak K„ Gibbs HurWtr J., Massague J., and Pavletidi N.P. 1995. Nature 376: 313. RusSO AA, Jeffrey P.O., and Paveltich M P. 1996. /Vci Struct Bid 3:696 ) Images prepared wiih MolScript, RobScnpt, and Raster 3D.

phosphate

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reorganization of the active site of the Oik, Once added, the phosphate group is bound by three argimnes, eacb from a different region around the catalytic cleft. These interactions fix the catalytic cleft in a conformation favorable for high activity.

The phosphorylation is performed by another kinase (called CAK). Many kinases are activated by a similar phosphorylation event. The two events that together activate Cdks—binding nf cyclin anrl phosphorylation—occur in (hat order. This is because cyclin binding not only increases the activity of the enzyme, but also makes tbe T loop accessible for phosphorylation by CAK,

Not Ail Regulation of Proteins Is Mediated by Allosteric Events

Some proteins are controlled in ways that do not involve altos tory. For example, one protein can recruit another to particular locations or substrates and in that way control what that protein acts on. When we discuss regulation of RNA polymerase (the enzyme that transcribes genes into mRNA), we will see that what (in that case) is usually meant by regulation is the choice of which gene is transcribed at any given time. This is done by regulatory proteins, which bind the DNA with one surface and the RNA polymerase with another. These interactions bring the enzyme to the gene (or genes) that bear appropriate binding sites for that particular regulator. This is an example of cooperative binding of proteins to DNA.

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