Циклинге тәуелді киназалар: Жасуша циклінің реттелуі мен эволюциясы

Class of enzymes

Cyclin dependent kinases (CDKs) are a predominant group of serine/threonine protein kinases involved in the regulation of the cell cycle and its progression, ensuring the integrity and functionality of cellular machinery. These regulatory enzymes play a crucial role in the regulation of eukaryotic cell cycle and transcription, as well as DNA repair, metabolism, and epigenetic regulation, in response to several extracellular and intracellular signals. They are present in all known eukaryotes, and their regulatory function in the cell cycle has been evolutionarily conserved. The catalytic activities of CDKs are regulated by interactions with CDK inhibitors (CKIs) and regulatory subunits known as cyclins. Cyclins have no enzymatic activity themselves, but they become active once they bind to CDKs. Without cyclin, CDK is less active than in the cyclin CDK heterodimer complex. CDKs phosphorylate proteins on serine (S) or threonine (T) residues. The specificity of CDKs for their substrates is defined by the S/T P X K/R sequence, where S/T is the phosphorylation site, P is proline, X is any amino acid, and the sequence ends with lysine (K) or arginine (R). This motif ensures CDKs accurately target and modify proteins, crucial for regulating cell cycle and other functions. Deregulation of the CDK activity is linked to various pathologies, including cancer, neurodegenerative diseases, and stroke. The evolutionary journey of CDKs has led to a diverse family with specific members dedicated to cell cycle phases or transcriptional control. For instance, budding yeast expresses six distinct CDKs, with some binding multiple cyclins for cell cycle control and others binding with a single cyclin for transcription regulation. In humans, the expansion to 20 CDKs and 29 cyclins illustrates their complex regulatory roles. Key CDKs such as CDK1 are indispensable for cell cycle control, while others like CDK2 and CDK3 are not. Moreover, transcriptional CDKs, such as CDK7 in humans, play crucial roles in initiating transcription by phosphorylating RNA polymerase II (RNAPII), indicating the intricate link between cell cycle regulation and transcriptional management. This evolutionary expansion from simple regulators to multifunctional enzymes underscores the critical importance of CDKs in the complex regulatory networks of eukaryotic cells. Leland H. Hartwell (b. 1929 ): Through studies of yeast in 1971, Heartwell identified crucial genes for cell division, outlining the cell cycle's stages and essential checkpoints to prevent cancerous cell division. Tim Hunt (b. 1943): Through studies of sea urchins in the 1980s, Hunt discovered the role of cyclins in the regulation of cell cycle phases through their cyclical synthesis and degradation. Sir Paul M. Nurse (b. 1949): In the mid 1970s, Nurse's studies uncovered the cdc2 gene in fission yeast, which is crucial for the progression of the cell cycle from G1 to S phase and from G2 to M phase. In 1987, he identified the corresponding gene in humans, CDK1, highlighting the conservation of cell cycle control mechanisms across species.

CDK is one of the estimated 800 human protein kinases. CDKs have low molecular weight, and they are known to be inactive by themselves. They are characterized by their dependency on the regulatory subunit, cyclin. The activation of CDKs also requires post translational modifications involving phosphorylation reactions. This phosphorylation typically occurs on a specific threonine residue, leading to a conformational change in the CDK that enhances its kinase activity. The activation forms a cyclin CDK complex which phosphorylates specific regulatory proteins that are required to initiate steps in the cell cycle. With cyclin, two alpha helices change position to enable ATP binding. One of them, the L12 helix located just before the T loop in the primary sequence, is transformed into a beta strand and helps to reorganize the T loop so that it no longer blocks the active site. The other alpha helix, known as the PSTAIRE helix, is reorganized and helps to change the position of the key amino acids in the active site. Cyclins can directly bind the substrate or localize the CDK to a subcellular area where the substrate is found. The RXL binding site  was crucial in revealing how CDKs selectively enhance activity toward specific substrates by facilitating substrate docking. Substrate specificity of S cyclins is imparted by the hydrophobic batch, which has affinity for substrate proteins that contain a hydrophobic RXL (or Cy) motif. The identity of the CDK activating kinase (CAK) that carries out this phosphorylation varies among different model organisms. The timing of this phosphorylation also varies; in mammalian cells, the activating phosphorylation occurs after cyclin binding, while in yeast cells, it occurs before cyclin binding. CAK activity is not regulated by known cell cycle pathways, and it is the cyclin binding that is the limiting step for CDK activation.]]

CDKs are essential for the control and regulation of the cell cycle. They are associated with small regulatory subunits regulatory subunits (CKSs). In mammalian cells, two CKSs are known: CKS1 and CKS2. These proteins are necessary for the proper functioning of CDKs, although their exact functions are not yet fully known. An interaction occurs between CKS1 and the carboxy terminal lobe of CDKs, where they bind together. This binding increases the affinity of the cyclin CDK complex for its substrates, especially those with multiple phosphorylation sites, thus contributing the promotion of cell proliferation.

Viruses can encode proteins with sequence homology to cyclins. One much studied example is K cyclin (or v cyclin) from Kaposi sarcoma herpes virus (see Kaposi's sarcoma), which activates CDK6. The vCyclin CDK6 complex promotes an accelerated transition from G1 to S phase in the cell by phosphorylating pRb and releasing E2F. This leads to the removal of inhibition on Cyclin E–CDK2's enzymatic activity. It is shown that vCyclin contributes to promoting transformation and tumorigenesis, mainly through its effect on p27 pSer10 phosphorylation and cytoplasmic sequestration.

Two protein types, p35 and p39, responsible for increasing the activity of CDK5 during neuronal differentiation in postnatal development. p35 and p39 play a crucial role in a unique mechanism for regulating CDK5 activity in neuronal development and network formation. The activation of CDK with these cofactors (p35 and p39) does not require phosphorylation of the activation loop, which is different from the traditional activation of many other kinases. This highlights the importance of activating CDK5 activity, which is critical for proper neuronal development, dendritic spine and synapse formation, as well as in response to epileptic events.

Proteins in the RINGO/Speedy group represent a standout bunch among proteins that don't share amino acid sequence homology with the cyclin family. They play a crucial role in activating CDKs. Originally identified in Xenopus, these proteins primarily bind to and activate CDK1 and CDK2, despite lacking homology to cyclins. What is particularly interesting, is that CDKs activated by RINGO/Speedy can phosphorylate different sites than those targeted by cyclin activated CDKs, indicating a unique mode of action for these non cyclin CDK activators.

Complications of developing a CDK drug include the fact that many CDKs are not involved in the cell cycle, but other processes such as transcription, neural physiology, and glucose homeostasis. More research is required, however, because disruption of the CDK mediated pathway has potentially serious consequences; while CDK inhibitors seem promising, it has to be determined how side effects can be limited so that only target cells are affected. As such diseases are currently treated with glucocorticoids. The comparison with glucocorticoids serves to illustrate the potential benefits of CDK inhibitors, assuming their side effects can be more narrowly targeted or minimized.