# PPP2R1A

## Overview
The PPP2R1A gene encodes the protein phosphatase 2 scaffold subunit Aα, a critical component of the protein phosphatase 2A (PP2A) complex, which is a serine/threonine phosphatase. This protein functions as a structural scaffold within the PP2A holoenzyme, facilitating the assembly of the catalytic and regulatory subunits, thereby playing a pivotal role in various cellular processes, including cell growth, division, and apoptosis (Haesen2016Recurrent; Janssens2008PP2A). The PPP2R1A gene is located on chromosome 19q13.33 and is characterized by its 15 tandem HEAT repeats, which are essential for its interaction with other subunits of the PP2A complex (Lambrecht2013Structure). Mutations in PPP2R1A have been implicated in several neurodevelopmental disorders and cancers, highlighting its significance in maintaining cellular homeostasis and its potential as a therapeutic target (Lei2023Prenatal; Wang2023PPP2R1A).

## Structure
The PPP2R1A gene encodes the scaffolding Aα subunit of protein phosphatase 2A (PP2A), a serine/threonine phosphatase involved in various cellular processes. The protein is composed of 589 amino acids and is located on chromosome 19q13.33. It features 15 tandem Huntington elongation A-subunit TOR (HEAT) repeats, each consisting of two α-helices connected by an intra-repeat loop. These HEAT repeats form domains that are crucial for binding the B and C subunits of the PP2A holoenzyme, which is a heterotrimer consisting of catalytic, scaffolding, and regulatory subunits (Qian2023Novel; Lambrecht2013Structure).

The PPP2R1A protein is an all-helical structural protein, maintaining the integrity of the phosphatase complex. Variants in the PPP2R1A gene, particularly those affecting the B-subunit-binding domain, have been associated with neurodevelopmental disorders. These variants can disrupt the protein's ability to bind with the B and C subunits, affecting the formation and function of PP2A holoenzymes (Qian2023Novel).

Post-translational modifications, such as methylation and phosphorylation, influence the activity and interactions of the PPP2R1A protein, although specific details on these modifications are not provided in the context (Lambrecht2013Structure).

## Function
The PPP2R1A gene encodes the Aα subunit of protein phosphatase 2A (PP2A), a critical serine/threonine phosphatase involved in numerous cellular processes. In healthy human cells, PP2A functions as a tumor suppressor by dephosphorylating key signaling proteins, thereby regulating cell growth, division, and apoptosis (McConechy2011Subtype‐specific; Haesen2016Recurrent). The Aα subunit acts as a scaffold, facilitating the assembly of the PP2A holoenzyme by linking the catalytic C subunit with various regulatory B-type subunits, which determine substrate specificity and subcellular localization (Groves1999The; Janssens2008PP2A).

PP2A is involved in critical signaling pathways, including the regulation of the cell cycle, DNA replication, transcription, and RNA splicing (Groves1999The). It also plays a role in maintaining cellular homeostasis by negatively regulating oncogenic pathways such as PI3K/Akt and stabilizing β-catenin, which can influence cell proliferation and tumorigenesis (McConechy2011Subtype‐specific). The Aα subunit's structural integrity is essential for the proper assembly and function of PP2A holoenzymes, which are crucial for maintaining normal cellular functions and preventing pathological conditions (Lenaerts2021The; Janssens2008PP2A).

## Clinical Significance
Mutations in the PPP2R1A gene are associated with a range of neurodevelopmental disorders (NDDs), including PPP2R1A-related neurodevelopmental disorder (NDD), also known as autosomal dominant intellectual developmental disorder-36 (MRD36). This condition is characterized by symptoms such as hypotonia, developmental delay, severe intellectual disability, ventriculomegaly, agenesis or hypoplasia of the corpus callosum, and facial dysmorphism. Additional features may include craniosynostosis, seizures, ptosis, ear-shape abnormalities, hearing loss, joint hypermobility, short stature, and scoliosis (Lei2023Prenatal; Lenaerts2021The).

Variants in PPP2R1A can disrupt the binding ability of the protein to the B and C subunits of the PP2A holoenzyme, affecting its activity. This disruption can lead to clinical manifestations such as microcephaly, macrocephaly, and intellectual disabilities (Qian2023Novel). The pathogenic mechanism is primarily a gain of function, although some variants result in a loss of function (Qian2023Novel).

PPP2R1A mutations have also been linked to pontocerebellar hypoplasia (PCH), microcephaly, and optic and peripheral nerve abnormalities, expanding the known clinical spectrum of PPP2R1A-related disorders (Roldán2023Advanced). The gene's high spontaneous mutation rate contributes to the clinical heterogeneity observed among patients (Zhang2019A).

## Interactions
PPP2R1A is a scaffold subunit of the protein phosphatase 2A (PP2A) complex, which plays a crucial role in various cellular processes. It interacts with the catalytic subunit PPP2CA and regulatory subunits such as PPP2R2A, facilitating the assembly of the PP2A holoenzyme (Wang2023PPP2R1A). PPP2R1A also interacts with the WAVE Regulatory Complex (WRC) and the NHSL1-containing WAVE Shell Complex (WSC), which are involved in cell migration persistence. This interaction is crucial for maintaining migration persistence, as demonstrated by its role in the lamellipodium edge where it interacts with the WSC, a site where Arp2/3 generates branched actin (Wang2023PPP2R1A).

Mutations in PPP2R1A, such as P179R, R183W, and W257C, impair its interaction with the WSC, affecting migration persistence and cell polarity, which are relevant for cancer progression (Wang2023PPP2R1A). These mutations also affect the binding to B subunit family members, leading to a loss of binding or complete abolition of binding, particularly with the W257A mutation (McConechy2011Subtype‐specific). The interaction of PPP2R1A with various subunits of the PP2A complex and its role in the RAC1-WAVE-Arp2/3 signaling pathway highlight its importance in cell migration and cancer-related pathways (Wang2023PPP2R1A).


## References


[1. (Zhang2019A) Yanghui Zhang, Haoxian Li, Hua Wang, Zhengjun Jia, Hui Xi, and Xiao Mao. A de novo variant identified in the ppp2r1a gene in an infant induces neurodevelopmental abnormalities. Neuroscience Bulletin, 36(2):179–182, September 2019. URL: http://dx.doi.org/10.1007/s12264-019-00430-4, doi:10.1007/s12264-019-00430-4. This article has 9 citations and is from a peer-reviewed journal.](https://doi.org/10.1007/s12264-019-00430-4)

[2. (Roldán2023Advanced) Mònica Roldán, Gregorio Alexander Nolasco, Lluís Armengol, Marcos Frías, Marta Morell, Manel García-Aragonés, Florencia Epifani, Jordi Muchart, María Luisa Ramírez-Almaraz, Loreto Martorell, Cristina Hernando-Davalillo, Roser Urreizti, and Mercedes Serrano. Advanced optical microscopy: unveiling functional insights regarding a novel ppp2r1a variant and its unreported phenotype. International Journal of Molecular Sciences, 24(18):13699, September 2023. URL: http://dx.doi.org/10.3390/ijms241813699, doi:10.3390/ijms241813699. This article has 0 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/ijms241813699)

[3. (McConechy2011Subtype‐specific) Melissa K McConechy, Michael S Anglesio, Steve E Kalloger, Winnie Yang, Janine Senz, Christine Chow, Alireza Heravi‐Moussavi, Gregg B Morin, Anne‐Marie Mes‐Masson, Mark S Carey, Jessica N McAlpine, Janice S Kwon, Leah M Prentice, Niki Boyd, Sohrab P Shah, C. Blake Gilks, and David G Huntsman. Subtype‐specific mutation of ppp2r1a in endometrial and ovarian carcinomas. The Journal of Pathology, 223(5):567–573, March 2011. URL: http://dx.doi.org/10.1002/path.2848, doi:10.1002/path.2848. This article has 110 citations.](https://doi.org/10.1002/path.2848)

[4. (Haesen2016Recurrent) Dorien Haesen, Layka Abbasi Asbagh, Rita Derua, Antoine Hubert, Stefanie Schrauwen, Yana Hoorne, Frédéric Amant, Etienne Waelkens, Anna Sablina, and Veerle Janssens. Recurrent ppp2r1a mutations in uterine cancer act through a dominant-negative mechanism to promote malignant cell growth. Cancer Research, 76(19):5719–5731, October 2016. URL: http://dx.doi.org/10.1158/0008-5472.can-15-3342, doi:10.1158/0008-5472.can-15-3342. This article has 88 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1158/0008-5472.can-15-3342)

[5. (Janssens2008PP2A) Veerle Janssens, Sari Longin, and Jozef Goris. Pp2a holoenzyme assembly: in cauda venenum (the sting is in the tail). Trends in Biochemical Sciences, 33(3):113–121, March 2008. URL: http://dx.doi.org/10.1016/j.tibs.2007.12.004, doi:10.1016/j.tibs.2007.12.004. This article has 328 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1016/j.tibs.2007.12.004)

[6. (Lambrecht2013Structure) Caroline Lambrecht, Dorien Haesen, Ward Sents, Elitsa Ivanova, and Veerle Janssens. Structure, Regulation, and Pharmacological Modulation of PP2A Phosphatases, pages 283–305. Humana Press, 2013. URL: http://dx.doi.org/10.1007/978-1-62703-562-0_17, doi:10.1007/978-1-62703-562-0_17. This article has 108 citations.](https://doi.org/10.1007/978-1-62703-562-0_17)

[7. (Lenaerts2021The) Lisa Lenaerts, Sara Reynhout, Iris Verbinnen, Frédéric Laumonnier, Annick Toutain, Frédérique Bonnet-Brilhault, Yana Hoorne, Shelagh Joss, Anna K. Chassevent, Constance Smith-Hicks, Bart Loeys, Pascal Joset, Katharina Steindl, Anita Rauch, Sarju G. Mehta, Wendy K. Chung, Koenraad Devriendt, Susan E. Holder, Tamison Jewett, Lauren M. Baldwin, William G. Wilson, Shelley Towner, Siddharth Srivastava, Hannah F. Johnson, Cornelia Daumer-Haas, Martina Baethmann, Anna Ruiz, Elisabeth Gabau, Vani Jain, Vinod Varghese, Ali Al-Beshri, Stephen Fulton, Oded Wechsberg, Naama Orenstein, Katrina Prescott, Anne-Marie Childs, Laurence Faivre, Sébastien Moutton, Jennifer A. Sullivan, Vandana Shashi, Suzanne M. Koudijs, Malou Heijligers, Emma Kivuva, Amy McTague, Alison Male, Yvette van Ierland, Barbara Plecko, Isabelle Maystadt, Rizwan Hamid, Vickie L. Hannig, Gunnar Houge, and Veerle Janssens. The broad phenotypic spectrum of ppp2r1a-related neurodevelopmental disorders correlates with the degree of biochemical dysfunction. Genetics in Medicine, 23(2):352–362, February 2021. URL: http://dx.doi.org/10.1038/s41436-020-00981-2, doi:10.1038/s41436-020-00981-2. This article has 24 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/s41436-020-00981-2)

[8. (Lei2023Prenatal) Tingying Lei, Li Zhen, Xin Yang, Min Pan, Fang Fu, Jin Han, Lushan Li, Dongzhi Li, and Can Liao. Prenatal diagnosis of ppp2r1a-related neurodevelopmental disorders using whole exome sequencing: clinical report and review of literature. Genes, 14(1):126, January 2023. URL: http://dx.doi.org/10.3390/genes14010126, doi:10.3390/genes14010126. This article has 2 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/genes14010126)

[9. (Wang2023PPP2R1A) Yanan Wang, Giovanni Chiappetta, Raphaël Guérois, Yijun Liu, Stéphane Romero, Daniel J. Boesch, Matthias Krause, Claire A. Dessalles, Avin Babataheri, Abdul I. Barakat, Baoyu Chen, Joelle Vinh, Anna Polesskaya, and Alexis M. Gautreau. Ppp2r1a regulates migration persistence through the nhsl1-containing wave shell complex. Nature Communications, June 2023. URL: http://dx.doi.org/10.1038/s41467-023-39276-w, doi:10.1038/s41467-023-39276-w. This article has 5 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/s41467-023-39276-w)

[10. (Qian2023Novel) Yanyan Qian, Yinmo Jiang, Ji Wang, Gang Li, Bingbing Wu, Yuanfeng Zhou, Xiu Xu, and Huijun Wang. Novel variants of ppp2r1a in catalytic subunit binding domain and genotype–phenotype analysis in neurodevelopmentally delayed patients. Genes, 14(9):1750, September 2023. URL: http://dx.doi.org/10.3390/genes14091750, doi:10.3390/genes14091750. This article has 1 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/genes14091750)

[11. (Groves1999The) Matthew R. Groves, Neil Hanlon, Patric Turowski, Brian A. Hemmings, and David Barford. The structure of the protein phosphatase 2a pr65/a subunit reveals the conformation of its 15 tandemly repeated heat motifs. Cell, 96(1):99–110, January 1999. URL: http://dx.doi.org/10.1016/s0092-8674(00)80963-0, doi:10.1016/s0092-8674(00)80963-0. This article has 344 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/s0092-8674(00)80963-0)