Biology:Cyclin-dependent kinase inhibitor protein

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Short description: Protein which inhibits cyclin-dependent kinase
Cyclin-dependent kinase inhibitor
PDB 1jsu EBI.jpg
Structure of the p27Kip1 cyclin-dependent-kinase inhibitor bound to the cyclin A-Cdk2 complex.[1]
Identifiers
SymbolCDI
PfamPF02234
InterProIPR003175
SCOP21jsu / SCOPe / SUPFAM

A cyclin-dependent kinase inhibitor protein (also known as CKIs, CDIs, or CDKIs) is a protein which inhibits the enzyme cyclin-dependent kinase (CDK) and Cyclin activity by stopping the cell cycle if there are unfavorable conditions, therefore, acting as tumor suppressors. Cell cycle progression is stopped by Cyclin-dependent kinase inhibitor protein at the G1 phase.[2] CKIs are vital proteins within the control system that point out whether the process of DNA synthesis, mitosis, and cytokines control one another. If a malfunction prevents the successful completion of DNA synthesis during the G1 phase, a signal is sent to delay or stop the progression to the S phase. Cyclin-dependent kinase inhibitor proteins are essential in the regulation of the cell cycle. If cell mutations surpass the cell cycle checkpoints during cell cycle regulation, it can result in various types of cancer.[3]

CKI Inactivation Process

Cyclin-dependent kinase inhibitor proteins work by inactivating the CDKs by degradation. The typical inactivation mechanism of the CDK/ Cyclin complex is based on binding a CDK inhibitor to the CDK cyclin complex and a partial conformational rotation of the CDK.[4] The cyclin is thus forced to release the T loop and detach from the CDK. Then, the CDK inhibitor initiates a small Helix into the cleft blocking the cleft and blocking the active site of the CDK. Eventually, it releases the ATP out of the aperture of the CDK and deactivates it. Cyclin-dependent kinase inhibitor proteins use ATP as a phosphate contributor to phosphorylate serine and threonine residues.[5][6]  

The typical inactivation mechanism of the CDK/ Cyclin complex is based on binding a CDK inhibitor to the CDK cyclin complex and a partial conformational rotation. The cyclin is thus forced to release the T loop and detach from the CDK. The CDK attaches its loop to the CKI stopping the activation of CDK/ Cyclin complex.

Human cells contain many different cyclins binding to different CDKs. CDKs and cyclins appear and activate at specific cell cycle phases. Seven cyclin-dependent kinase inhibitor proteins have been identified. They are p15, p16, p18, p19, p21, p27, and p57.[7] These cyclin-dependent kinase inhibitor protein emerges only in their specific cell cycle phase.[7] Each Cyclin/CDK complex are specific to the part of the cell cycle phase. Each CDK and cyclin can be identified based on the location of the cell cycle. CKIs fall within two categories; those that inhibit CDKI, CDK2, and CDK5 and those that inhibit CDK4 and CDK6. These checkpoints' cell cycle blocks at both the G1/S and G2/M checkpoints are consistent with the inhibition profile of the enzymes.

Discovery

The discovery of Cyclin-dependent kinase inhibitor proteins in 1990 opened the door in how we think about cell cycle control. It has steered to various other fields of study such as developmental biology, cell biology and cancer research.[8] The discovery of the first CKIs in yeast (Far1) and P21 in mammals has led to research on family of molecules.[8] Further research has demonstrates that Cdks, cyclins and CKIs play essential roles in processes such as transcription, epigenetic regulation, metabolism, stem cell self-renewal, neuronal functions and spermatogenesis.[2]

In mammals, p27, a cyclin-dependent kinase inhibitor protein, helps control CDK activity in G1. Also, the INK4 proteins help stop the G1-CDK activity when they encounter anti-proliferative signals within the environment.[5]  CKIs help promote the specific inhibitory signals that contain the cell from entering the S phase. In budding yeast, SIC 1 and Roughex, RUX, in Drosophila possess the same contributions that contribute to the stability of G1 cells. They are expressed in higher numbers in G1 cells to make sure that no S or M CDKs are in the cell.[5]

Structure

In the cyclin-dependent kinase (CDK) family or CDK, Cyclin, and CKIs, serine/threonine kinases play an integral role in regulating the eukaryotic cell cycle. The structure of CDK2-CyclinA and p27 is determined by crystallography, demonstrating that the inhibitor of p27 stretches at the top of the Cyclin-CDK complex. The amino terminal of p27 has an RXL motif exhibiting a hydrophobic patch of cyclin A. The carboxyl-terminal end of the p27 fragment interacts with the beta sheet of CDKs, causing interference of the structure; p27 slides into the ATP- binding site of CDK2 and inhibits ATP binding.[5]

Clinical significance

Role in cancer: Cyclin-dependent kinase inhibitors (CKIs) mutants are frequent in human cancers. The function of CKI is to stop cell growth when there are mistakes due to DNA damage. Once a cell is stopped at a checkpoint due to DNA damage, either the damage is repaired or the cell is induced to perform apoptosis.[9] However, if CKI’s mutations don’t stop the cell, the Cyclin D is transcribed. It moves into the cytoplasm and eventually activates a specific cyclin-dependent kinase (CDK). The active cyclin/CDK complex then phosphorylates proteins, activates them, and sends the cell into the next phase of the cell cycle. Since the cell with damaged DNA is not stopped, the cell eventually moves out of the G1 checkpoint and prepares for DNA synthesis. When there is uncontrolled cell growth, it can lead to cancer cells due to the inactivation of the CKIs.

Associated gene and target

Protein Gene Target
p16 CDKN2A Cyclin-dependent kinase 4, Cyclin-dependent kinase 6
p15 CDKN2B Cyclin-dependent kinase 4
p18 CDKN2C Cyclin-dependent kinase 4, Cyclin-dependent kinase 6
p19 CDKN2D Cyclin-dependent kinase 4, Cyclin-dependent kinase 6
p21 / WAF1 CDKN1A[10] Cyclin E1/Cyclin-dependent kinase 2
p27 CDKN1B Cyclin D3/Cyclin-dependent kinase 4, Cyclin E1/Cyclin-dependent kinase 2
p57 CDKN1C Cyclin E1/Cyclin-dependent kinase 2
CDKN3 Cyclin-dependent kinase 2

References

  1. ↑ "Crystal structure of the p27Kip1 cyclin-dependent-kinase inhibitor bound to the cyclin A-Cdk2 complex". Nature 382 (6589): 325–331. July 1996. doi:10.1038/382325a0. PMID 8684460. Bibcode: 1996Natur.382..325R. 
  2. ↑ 2.0 2.1 "Cdks, cyclins and CKIs: roles beyond cell cycle regulation". Development 140 (15): 3079–3093. August 2013. doi:10.1242/dev.091744. PMID 23861057. 
  3. ↑ "The Cell Cycle" (in en). Physiology of the Gastrointestinal Tract. Elsevier. 2018. pp. 197–219. doi:10.1016/b978-0-12-809954-4.00008-6. ISBN 978-0-12-809954-4. https://linkinghub.elsevier.com/retrieve/pii/B9780128099544000086. Retrieved 2023-05-02. 
  4. ↑ Molecular Biology of the Cell. 2017-08-07. doi:10.1201/9781315735368. ISBN 9781315735368. http://dx.doi.org/10.1201/9781315735368. 
  5. ↑ 5.0 5.1 5.2 5.3 The cell cycle : principles of control. London, UK: New Science Press. 2007. pp. 40. ISBN 978-0-9539181-2-6. 
  6. ↑ "Cyclin-dependent kinases". Genome Biology 15 (6): 122. 2014. doi:10.1186/gb4184. PMID 25180339. 
  7. ↑ 7.0 7.1 "The expression of cyclin-dependent kinase inhibitors p15, p16, p21, and p27 during ovarian follicle growth initiation in the mouse". Reproductive Biology and Endocrinology 1 (1): 41. May 2003. doi:10.1186/1477-7827-1-41. PMID 12777178. 
  8. ↑ 8.0 8.1 "Inhibitors in control" (in en). Trends in Cell Biology 9 (3): 122. March 1999. doi:10.1016/S0962-8924(98)01496-2. https://linkinghub.elsevier.com/retrieve/pii/S0962892498014962. 
  9. ↑ "Cell Cycle Regulation by Checkpoints" (in en), Cell Cycle Control, Methods in Molecular Biology (New York, NY: Springer New York) 1170: pp. 29–40, 2014, doi:10.1007/978-1-4939-0888-2_2, ISBN 978-1-4939-0887-5, PMID 24906307 
  10. ↑ "Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors". Oncogene 18 (3): 813–822. January 1999. doi:10.1038/sj.onc.1202367. PMID 9989833. 

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