The role of structural disorder in cell cycle regulation, related clinical proteomics, disease development and drug targeting

Abstract

Understanding the molecular mechanisms of the regulation of cell cycle is a central issue in molecular cell biology, due to its fundamental role in the existence of cells. The regulatory circuits that make decisions on when a cell should divide are very complex and particularly subtly balanced in eukaryotes, in which the harmony of many different cells in an organism is essential for life. Several hundred proteins are involved in these processes, and a great deal of studies attests that most of them have functionally relevant intrinsic structural disorder. Structural disorder imparts many functional advantages on these proteins, and we discuss it in detail that it is involved in all key steps from signaling through the cell membrane to regulating transcription of proteins that execute timely responses to an ever-changing environment.

Keywords:

• cancer
• cell-cycle
• checkpoint
• post-translational modification
• protein disorder
• signal transduction

Financial & competing interests disclosure

P Tompa is supported by the Research Foundation Flanders (FWO). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Progression through the phases of the cell cycle is crucial for the stability of the cells and its correct regulation is the cornerstone of the integrity of the whole organism. Proteins involved in cell cycle regulation play primary roles in several diseases, the most important of which is cancer. Tumor genesis is promoted by either the aberrant expression of positive regulators, such as cyclins, or the loss of function of negative regulators, such as cyclin-dependent kinase (CDK) inhibitors (CKIs).

• Intrinsically disordered proteins or regions (IDPs/IDRs) function without possessing a stable three-dimensional structure and are among the main players in cell cycle regulation. IDPs function either as disordered polypeptide chains (entropic chains) or via molecular recognition (as shorter or longer binding motifs), which entails manifold functional advantages.

• Proteins annotated to cell cycle have significantly different frequency distribution from all human proteins. This distribution bias shows a strong association of structural disorder with cell cycle. Highly disordered proteins are involved in the regulation of G1/S and G2/M transitions, and while the small regulator, inhibitor proteins are abundant among disordered proteins in G1/S, longer proteins with the potential to have adaptor, complex and bridge forming function are dominant among IDPs in G2/M transition.

• The activity of different Cdk/cyclin complexes is strictly controlled, primarily by CKIs. The most thoroughly studied group of CKIs is the CIP/KIP family that comprises p21Cip1, p27Kip1 and p57Kip2. The CIP/KIP proteins are IDPs and although they inhibit multiple CDK/cyclin complexes, they also facilitate the assembly and nuclear transport of the CDK 4(6)/cyclin-D complexes.

• A central player in cell-cycle regulation is p53, which is activated by DNA damage, heat shock and other stress signals. Activation of p53 results in changes of several genes that intervene in the progression of the cell cycle leading to cell cycle arrest and apoptosis. Its disordered N-terminal domain is involved in the binding of transcriptional coactivators and corepressors and is essential for binding with Mdm2.

• Phosphorylation participates in the regulation of almost all cellular processes, and it has been shown that phosphorylation sites preferentially occur in disordered regions where they are accessible for the modifying enzyme. Changes in phosphorylation pattern may increase the sensitivity and robustness of the cellular response and may promote the switch-like behavior of a cellular process.

• The preponderance of structural disorder is an apparent impediment to drug development efforts, but because IDPs most often function by protein–protein interactions, their interfaces might in principle be targeted by small molecules. IDPs most often engage in a special type of interaction, mediated by their short recognition elements, which bind in a hydrophobic pocket of the partner molecule, suggesting that the binding partners of IDPs might be successfully targeted by small molecules. Four of the eight drugs against protein–protein interaction interfaces target a complex that involves a disordered and a structured partner.

• The potential targets, that is, disorder-related disease-associated proteins can be identified in high-throughput (HTS) proteomic analyses. There are numerous novel techniques with the potential to provide valuable biological information related to IDPs in the physiological or pathological process of cell cycle. HTS proteomic studies are always coupled with extended bioinformatics methods to analyze and to store the large amount of output data.