# PCNT

## Overview
Pericentrin, encoded by the PCNT gene, is a critical scaffold protein predominantly localized to the centrosome, where it plays a vital role in cell division and the structural integrity of cells. The PCNT gene is responsible for the synthesis of pericentrin, a protein that is essential for the organization of the pericentriolar material and the proper functioning of the mitotic spindle. This protein is involved in the nucleation and anchoring of microtubules, facilitating accurate chromosome segregation and cell cycle progression. Pericentrin is also crucial in the formation and function of primary cilia, which are key for cellular signaling and sensing external stimuli. Disruptions in the function of pericentrin can lead to a variety of severe developmental and cellular disorders, highlighting its importance in human biology (Zimmerman2004Mitosis-specific; Delaval2009Pericentrin).

## Structure
Pericentrin (PCNT) is a large, scaffold protein that is crucial in the organization of the pericentriolar material in centrosomes. The protein is composed of multiple coiled-coil regions, which are predicted to be largely α-helical in structure. These regions include CC1, CC2, and CC3, with molecular masses of approximately 35 kDa, 17 kDa, and 40 kDa respectively. Circular dichroism analyses have confirmed the α-helical structure of these regions, with CC1 showing 69-81% α-helicity, CC2 showing 76-89% α-helicity, and CC3 showing 63-67% α-helicity (Kim2017Over-Production). The secondary structure of these regions is predominantly α-helical with less than 5% β-strand content. 

The tertiary structure of at least one of these coiled-coil regions, CC2, has been further elucidated through X-ray crystallography, which provided insights into its three-dimensional folding (Kim2017Over-Production). However, detailed information on the quaternary structure, specific domains other than coiled-coil, prominent folds, common post-translational modifications, or splice variant isoforms of PCNT is not provided in the available literature. Thus, while the primary and secondary structures of PCNT are well-characterized, further studies are needed to fully understand its tertiary and quaternary structures.

## Function
Pericentrin, encoded by the PCNT gene, is a pivotal component of the centrosome in human cells, primarily involved in the organization and function of the mitotic spindle during cell division. It plays a critical role in nucleating and anchoring microtubules at the centrosome, which is essential for proper spindle assembly and chromosome segregation during mitosis (Zimmerman2004Mitosis-specific; Delaval2009Pericentrin). Pericentrin's interaction with γ-tubulin and the γ-tubulin ring complex facilitates the nucleation of microtubules, a process crucial for maintaining genomic stability and ensuring accurate cell division (Zimmerman2004Mitosis-specific; Delaval2009Pericentrin).

In addition to its role in mitosis, pericentrin is involved in the assembly and function of primary cilia, cellular structures important for signal transduction and sensing the extracellular environment. It localizes to the base of primary cilia, influencing cilia formation and function, which is vital for cell signaling and sensory functions (Delaval2009Pericentrin).

Disruption of pericentrin function can lead to severe cellular defects, including disorganized spindles, abnormal cell cycle checkpoint signaling, and defects in spindle orientation. These cellular anomalies can result in conditions like primordial dwarfism, cancer progression, and mental disorders due to compromised cell division, chromosome segregation, and stem cell renewal (Zimmerman2004Mitosis-specific; Delaval2009Pericentrin).

## Clinical Significance
Mutations in the PCNT gene are primarily associated with Microcephalic Osteodysplastic Primordial Dwarfism Type II (MOPD II), a rare autosomal recessive disorder characterized by extreme pre-and postnatal growth retardation, microcephaly, and skeletal dysplasia. Individuals with MOPD II typically exhibit significantly reduced stature, with an average adult height of about 100 cm, and may also display a variety of bone and dental anomalies. Despite their small head size, brain development is mostly normal, although some may experience serious mental retardation (Rauch2008Mutations).

PCNT mutations have also been linked to a spectrum of cerebrovascular diseases, including cerebral aneurysms and Moyamoya disease, which are significant causes of morbidity and mortality in these patients. The exact molecular mechanisms linking PCNT mutations to these vascular issues are not fully understood (Petraroli2023Case; Li2015Identification).

Furthermore, some patients with PCNT mutations exhibit anemia, bone marrow failure, T-cell clonality, myelodysplasia, acute myeloid leukemia, thrombocytosis, and leukocytosis, underscoring the gene's broader impact on cellular functions beyond skeletal development (Li2015Identification).

## Interactions
Pericentrin (PCNT) interacts with a variety of proteins, playing a crucial role in cellular structures and processes. It forms complexes with intraflagellar transport (IFT) proteins and polycystin-2 (PC2), essential for the assembly of primary cilia at centrioles and basal bodies (Jurczyk2004Pericentrin). PCNT also interacts with Cep57 and AKAP9 through its PACT domain, which is significant for its localization and function at centrioles, impacting centrosome and microtubule organization during cell division (Watanabe2019The). Additionally, PCNT is phosphorylated by PLK1, which is crucial for recruiting pericentriolar matrix (PCM) proteins like CEP192, GCP-WD, and γ-tubulin, facilitating centrosome maturation and spindle formation (Lee2011PLK1). The interaction between PCNT and CEP215 is vital for centrosome maturation and spindle pole formation during mitosis, independent of PLK1 phosphorylation (Kim2014Importance). PCNT also interacts with γ-tubulin ring complexes (γ TuRCs), influencing mitotic spindle assembly (Zimmerman2004Mitosis-specific). Furthermore, PCNT interacts with cytoplasmic dynein through the dynein light intermediate chain 1 (LIC1), facilitating the transport of the actively translating PCNT mRNA along microtubules toward the centrosome (Sepulveda2018Co-translational). These interactions underscore the multifunctional role of PCNT in cell division and structural organization.


## References


[1. (Zimmerman2004Mitosis-specific) Wendy C. Zimmerman, James Sillibourne, Jack Rosa, and Stephen J. Doxsey. Mitosis-specific anchoring of γ tubulin complexes by pericentrin controls spindle organization and mitotic entry. Molecular Biology of the Cell, 15(8):3642–3657, August 2004. URL: http://dx.doi.org/10.1091/mbc.e03-11-0796, doi:10.1091/mbc.e03-11-0796. (238 citations) 10.1091/mbc.e03-11-0796](https://doi.org/10.1091/mbc.e03-11-0796)

[2. (Kim2017Over-Production) Min Kim, Jeong Park, Yeowon Sim, Doheum Kim, Jeong Sim, and SangYoun Park. Over-production, crystallization, and preliminary x-ray crystallographic analysis of a coiled-coil region in human pericentrin. Crystals, 7(10):296, October 2017. URL: http://dx.doi.org/10.3390/cryst7100296, doi:10.3390/cryst7100296. (0 citations) 10.3390/cryst7100296](https://doi.org/10.3390/cryst7100296)

[3. (Watanabe2019The) Koki Watanabe, Daisuke Takao, Kei K Ito, Mikiko Takahashi, and Daiju Kitagawa. The cep57-pericentrin module organizes pcm expansion and centriole engagement. Nature Communications, February 2019. URL: http://dx.doi.org/10.1038/s41467-019-08862-2, doi:10.1038/s41467-019-08862-2. (65 citations) 10.1038/s41467-019-08862-2](https://doi.org/10.1038/s41467-019-08862-2)

[4. (Kim2014Importance) Seongjae Kim and Kunsoo Rhee. Importance of the cep215-pericentrin interaction for centrosome maturation during mitosis. PLoS ONE, 9(1):e87016, January 2014. URL: http://dx.doi.org/10.1371/journal.pone.0087016, doi:10.1371/journal.pone.0087016. (91 citations) 10.1371/journal.pone.0087016](https://doi.org/10.1371/journal.pone.0087016)

[5. (Delaval2009Pericentrin) Benedicte Delaval and Stephen J. Doxsey. Pericentrin in cellular function and disease. Journal of Cell Biology, 188(2):181–190, December 2009. URL: http://dx.doi.org/10.1083/jcb.200908114, doi:10.1083/jcb.200908114. (156 citations) 10.1083/jcb.200908114](https://doi.org/10.1083/jcb.200908114)

[6. (Li2015Identification) Fei-Feng Li, Xu-Dong Wang, Min-Wei Zhu, Zhi-Hong Lou, Qiong Zhang, Chun-Yu Zhu, Hong-Lin Feng, Zhi-Guo Lin, and Shu-Lin Liu. Identification of two novel critical mutations in pcnt gene resulting in microcephalic osteodysplastic primordial dwarfism type ii associated with multiple intracranial aneurysms. Metabolic Brain Disease, 30(6):1387–1394, August 2015. URL: http://dx.doi.org/10.1007/s11011-015-9712-y, doi:10.1007/s11011-015-9712-y. (24 citations) 10.1007/s11011-015-9712-y](https://doi.org/10.1007/s11011-015-9712-y)

[7. (Sepulveda2018Co-translational) Guadalupe Sepulveda, Mark Antkowiak, Ingrid Brust-Mascher, Karan Mahe, Tingyoung Ou, Noemi M Castro, Lana N Christensen, Lee Cheung, Xueer Jiang, Daniel Yoon, Bo Huang, and Li-En Jao. Co-translational protein targeting facilitates centrosomal recruitment of pcnt during centrosome maturation in vertebrates. eLife, April 2018. URL: http://dx.doi.org/10.7554/elife.34959, doi:10.7554/elife.34959. (90 citations) 10.7554/elife.34959](https://doi.org/10.7554/elife.34959)

[8. (Rauch2008Mutations) Anita Rauch, Christian T. Thiel, Detlev Schindler, Ursula Wick, Yanick J. Crow, Arif B. Ekici, Anthonie J. van Essen, Timm O. Goecke, Lihadh Al-Gazali, Krystyna H. Chrzanowska, Christiane Zweier, Han G. Brunner, Kristin Becker, Cynthia J. Curry, Bruno Dallapiccola, Koenraad Devriendt, Arnd Dörfler, Esther Kinning, André Megarbane, Peter Meinecke, Robert K. Semple, Stephanie Spranger, Annick Toutain, Richard C. Trembath, Egbert Voss, Louise Wilson, Raoul Hennekam, Francis de Zegher, Helmuth-Günther Dörr, and André Reis. Mutations in the pericentrin ( pcnt ) gene cause primordial dwarfism. Science, 319(5864):816–819, February 2008. URL: http://dx.doi.org/10.1126/science.1151174, doi:10.1126/science.1151174. (330 citations) 10.1126/science.1151174](https://doi.org/10.1126/science.1151174)

[9. (Jurczyk2004Pericentrin) Agata Jurczyk, Adam Gromley, Sambra Redick, Jovenal San Agustin, George Witman, Gregory J. Pazour, Dorien J.M. Peters, and Stephen Doxsey. Pericentrin forms a complex with intraflagellar transport proteins and polycystin-2 and is required for primary cilia assembly. The Journal of Cell Biology, 166(5):637–643, August 2004. URL: http://dx.doi.org/10.1083/jcb.200405023, doi:10.1083/jcb.200405023. (218 citations) 10.1083/jcb.200405023](https://doi.org/10.1083/jcb.200405023)

[10. (Petraroli2023Case) Maddalena Petraroli, Antonio Percesepe, Maria Piane, Francesca Ormitti, Eleonora Castellone, Margherita Gnocchi, Giulia Messina, Luca Bernardi, Viviana Dora Patianna, Susanna Maria Roberta Esposito, and Maria Elisabeth Street. Case report: short stature, kidney anomalies, and cerebral aneurysms in a novel homozygous mutation in the pcnt gene associated with microcephalic osteodysplastic primordial dwarfism type ii. Frontiers in Endocrinology, May 2023. URL: http://dx.doi.org/10.3389/fendo.2023.1018441, doi:10.3389/fendo.2023.1018441. (1 citations) 10.3389/fendo.2023.1018441](https://doi.org/10.3389/fendo.2023.1018441)

[11. (Lee2011PLK1) Kwanwoo Lee and Kunsoo Rhee. Plk1 phosphorylation of pericentrin initiates centrosome maturation at the onset of mitosis. Journal of Cell Biology, 195(7):1093–1101, December 2011. URL: http://dx.doi.org/10.1083/jcb.201106093, doi:10.1083/jcb.201106093. (307 citations) 10.1083/jcb.201106093](https://doi.org/10.1083/jcb.201106093)