Polo-Like Kinase 1 (PLK-1)

Victoria Osborne '24 and Justin Perdomo '24

Contents:

I. Introduction

Polo-like kinase 1, otherwise known as PLK1, is a regulator protein that operates primarily in the cell cycle's G2 and M phases. In these phases, PLK1 acts as a kinase to set up other proteins to pull apart chromosome pairs to begin anaphase with its removal. Our interest in the protein comes from its potential to be a target in cancer therapy. This is mostly due to its role during the cell cycle leading to the eventual replication of cells. PLK1 has also been found to be more highly in multiple cancer cell types.

The first role of PLK1 during the cell cycle is during centrosome maturation in which PLK1 and Aurora A Kinase are recruited by CEP192. The PLK1 acts as docking sites for gamma-tubulin ring complexes. Through the interactions PLK1 gets located to the centrosomes. During mitosis entry, PLK1's main role is to act as a kinase and to activate other proteins in order to eventually phosphorylate CDC25C, which then activates the CDK complex. Its final main role is involved in kinetochore-microtubule attachment. It gets recruited to the kinetochore, and then it gets phosphorylated in order to promote the mitotic checkpoint complex. When the chromosomes are aligned, PLK1 gets removed and then anaphase is initiated.

PLK1Domains
Figure 1: PLK-1 involvement in steps of the cell cycle and mitosis. Acquired from Polo-like Kinase 1 (PLK1) Signaling in Cancer and Beyond.

II. General Structure

PLK1 is a heterodimer with a N-terminal kinase domain and a C-terminal polo-box domain. The is involved in phosphorylation. The , which contains 2 polo-boxes, functions to bind other proteins, including Map205, which was used to produce the depicted .

The polo-box domain takes up residues 360 to 595 and the kinase domain takes up 17 to 312. Within the kinase domain, PLK1 contains a N-terminal lobe, and a larger C-terminal lobe, and is connected to each other by a hinge. The polo-box domain contains 2 linkers that connect the other 3 regions of the domain. The N-terminal polo cap connects to polo-box 1 by polo-box 2 until it eventually approaches linker 1, which serves as the between the polo cap and polo-box 1. Polo-box 1 then to polo-box 2 via linker 2.

PLK1Domains

Figure 2: Strand of domains and residues of PLK-1. From Structural Basis for the Inhibition of PLK-1.

III. Activating Regions

The purpose of the polo-boxes is to act as a binding site for other proteins through phosphopeptide bonds, which involve both protein-protein and protein-phosphate . The recruitment of particular proteins to the polo-box can aid PLK1 function in the kinase domain, allowing it to phosphorylate other proteins in order to then regulate their functions. When PLK1 is not connected to any other proteins, the polo-box domain binds to the N-terminal domain of the kinase domain.

IV. Cancer Treatment Target

Due to the nature of PLK1 being involved in changing phases during the cell cycle, it has been proposed as a potential target for cancer therapy. Multiple studies discuss how PLK1 has been observed in higher levels in multiple different types of cancers. These findings suggest that targeting the protein and inactivating it could stall mitosis, therefore the divsion of cancerous cells, by preventing them from going into anaphase. This concept also falls in line with how cancer can be caused by the malfunctioning of a regulator or promoter and a malfunction of a guardian that otherwise would repress its expression.

V. References

Cheng, K. Y., Lowe, E. D., Sinclair, J., Nigg, E. A., & Johnson, L. N. (2003). The Crystal Structure of the Human Polo-Like Kinase-1 Polo Box Domain and Its Phospho-Peptide Complex. The EMBO Journal, 22(21), 5757-5768. https://doi.org/10.1093/emboj/cdg558.

de Carcer, G., Venkateswaran, S.V., Salgueiro, L. et al. Plk1 Overexpression Induces Chromosomal Instability and Suppresses Tumor Development. Nat Commun 9, 3012 (2018). https://doi-org.libproxy.kenyon.edu/10.1038/s41467-018-05429-5.

Ehlen, A., Martin, C., Miron, S. et al. Proper Chromosome Alignment Depends on BRCA2 Phosphorylation by PLK1. Nat Commun 11, 1819 (2020). https://doi-org.libproxy.kenyon.edu/10.1038/s41467-020-15689-9

Iliaki, S., Beyaert, R., & Afonina, I. S. (2021). Polo-Like Kinase 1 (PLK1) Signaling in Cancer and Beyond. Biochemical Pharmacology, 193, 114747. https://doi.org/10.1016/j.bcp.2021.114747.

Liu, Z., Sun, Q., & Wang, X. (2017). PLK1, A Potential Target for Cancer Therapy. Translational Oncology, 10(1), 22-32. https://doi.org/10.1016/j.tranon.2016.10.003.

Rosie Elizabeth Ann Gutteridge, Mary Ann Ndiaye, Xiaoqi Liu, Nihal Ahmad; Plk1 Inhibitors in Cancer Therapy: From Laboratory to Clinics. Mol Cancer Ther. 1 July 2016; 15 (7): 1427-1435. https://doi.org/10.1158/1535-7163.MCT-15-0897

Xu, J., Shen, C., Wang, T., & Quan, J. (2013). Structural Basis for the Inhibition of Polo-Like Kinase 1. Nature structural & molecular biology, 20(9r), 1047-1053. https://doi.org/10.1038/nsmb.2623.

Elling, R. A., Fucini, R. V., & Romanowski, M. J. (2008). Structures of the Wild-Type and Activated Catalytic Domains of Brachydanio Rerio Polo-Like Kinase 1 (Plk1): Changes in the Active-Site Conformation and Interactions with Ligands. Acta Crystallographica. Section D, Biological Crystallography, 64(Pt 9), 909-918. https://doi.org/10.1107/S0907444908019513

Yung Ho Lee, Jeong-Ah Hwang, Sun-Ok Kim, Jung Hee Kim, Sang Chul Shin, Eunice EunKyeong Kim, Kyung S. Lee, Kunsoo Rhee, Byeong Hwa Jeon, Jeong Kyu Bang, Hyunjoo Cha-Molstad, Nak-Kyun Soung, Jae-Hyuk Jang, Sung-Kyun Ko, Hee Gu Lee, Jong Seog Ahn, Yong Tae Kwon, Bo Yeon Kim, Phosphorylation of Human Enhancer Filamentation 1 (HEF1) Stimulates Interaction with Polo-Like Kinase 1 Leading to HEF1 Localization to Focal Adhesions, Journal of Biological Chemistry, Volume 293, Issue 3, 2018, Pages 847-862, ISSN 0021-9258, https://doi.org/10.1074/jbc.M117.802587.

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