Cyclin box

The cyclins were originally defined as proteins that show cyclic concentration variations during the cell cycle (Fig. 13.7). A classifying feature of the cyclins today is the cyc-lin box, a conserved domain of ca. 100 amino acids. Binding to the corresponding CDK takes place via the cyclin box. 

Cyclins in higher eukaryotes are classified and divided into eight families, from A to H, based on sequence relationships and the time of appearance in the cell cycle. Although cyclins are a family of diverse proteins, they all have a common region of about 100 amino acids in the C-terminal part. This domain is the cyclin box. 

Plate 25, ref. 9 shows, on the left, the structure of the p27 " cyclin-dependent-kinase inhibitor protein-1, bound to the cyclin A-Cdkl complex, and on the right is introduced the cyclin-box motif of cyclin A, to which the p27 "i inhibitor binds. The key binding motif of inhibitory proteins for cyclin-Cdks appears to be conserved. Disruption of the p27 > gene in mice removes the negative control and leads to cell proliferation in many tissues. 

Right Structural scheme of the cyclin-box motif of cyclin A to which the p27kif-t binds. The peptidebinding groove of cyclin A. in purple, is filled by the green balls of the p27 - protein. The cyclin box is a rather common, stable structural fold, which comprises a bundle of five tandemly repeated a-helices. On the surface of the cyclin box are clusters of conserved residues, which, in the case of the cyclin A-Cdkl pair, have been shown to be part of the interaction surface of the cyclin with the cognate kinase. 

TFIIB is arranged in two domains, both of which have the cyclin fold described in Chapter 6. Both domains bind to the TBP-TATA box complex at the C-terminal stirrup and helix of TBP. The phosphate and sugar moities of DNA form extensive non-sequence-specific contacts with TFIIB both upstream and downstream of the middle of the TATA box. 

Fig. 6.1. The F-box motif in human Skp2, budding yeast Cdc4, and human cyclin F (CycF). The conserved amino acids are highlighted.

SCF -CyclinE-E2 complexes [66, 85, 103]. In all cases, no intermolecular collision was found in the final models. The substrate-binding domains of all three F-box proteins are positioned on the same side of the SCF complex as the E2. In addition, these domains are all oriented toward the E2 active site. Remarkably, the positions of the WD40 domain in the and SCF models are strikingly... 

Strohmaier, H., Spruck, C. H., Kaiser, P., Won, K. A., Sangfelt, O., and Reed, S. I. (2001). Human F-box protein hCdc4 targets cyclin E for proteolysis and is mutated in a breast cancer cell line. Nature 413, 316-22. 

The cyclosome (or APC) is a high molecular weight complex that degrades proteins containing a specific recognition sequence, the destruction box (see chapter 13.2.4). Substrates are cell cycle regulators as e.g. cyclins, kinase inhibitors and spindle-associated proteins. Importantly, some forms of the cyclosome require phosphorylation in order to be active (fig. 2.15B). It is still unclear which of the many subunits carries the E3 enzyme activity. 

---