# EGLN1

## Overview
EGLN1 is a gene that encodes the protein prolyl hydroxylase domain-containing protein 2 (PHD2), which is a key regulator in the cellular response to oxygen levels. PHD2 is a member of the 2-oxoglutarate-dependent dioxygenase family and functions primarily as a prolyl hydroxylase. It plays a crucial role in the oxygen-sensing pathway by hydroxylating hypoxia-inducible factor 1-alpha (HIF-1α) under normoxic conditions, marking it for degradation and thus preventing the activation of hypoxia-responsive genes when oxygen is sufficient (Aggarwal2010EGLN1; Berra2003HIF). The protein is characterized by a C-terminal prolyl hydroxylase domain and an N-terminal MYND-type zinc finger domain, which is unique to PHD2 and essential for its function (Arsenault2016The). PHD2's activity is modulated by various post-translational modifications and interactions with other proteins, highlighting its complex regulatory role in cellular adaptation to hypoxia (Chowdhury2011Studies; Haffey2009iTRAQ). Alterations in EGLN1 have been linked to several clinical conditions, including cancer and erythrocytosis, underscoring its significance in human health and disease (Kato2005Induction; Gangat2022Erythrocytosis).

## Structure
The EGLN1 gene encodes the prolyl hydroxylase domain-containing protein 2 (PHD2), which plays a crucial role in the cellular response to hypoxia. PHD2 is characterized by a C-terminal prolyl hydroxylase domain and an N-terminal MYND-type zinc finger domain. The zinc finger domain is essential for the protein's function, facilitating the hydroxylation of hypoxia-inducible factor α (HIF-α) by recruiting PHD2 to the HSP90 pathway (Arsenault2016The). The prolyl hydroxylase domain features a double-stranded β-helix core fold supported by surrounding α-helices, typical of 2-oxoglutarate-dependent dioxygenases (Delamare2023Characterization).

PHD2 undergoes post-translational modifications, such as S-nitrosylation, which can modulate its activity. This modification involves the addition of an NO group to cysteine residues, potentially affecting the enzyme's function (Chowdhury2011Studies). The protein also has several isoforms resulting from alternative splicing, which may influence its activity and stability (Chowdhury2011Studies).

The zinc finger domain of PHD2 is absent in its homologs PHD1 and PHD3, highlighting its unique role in PHD2's function (Arsenault2016The). This domain is crucial for the protein's interaction with the PXLE motif, and mutations in this region can lead to impaired function and developmental defects (Arsenault2016The).

## Function
EGLN1, also known as prolyl hydroxylase domain-containing protein 2 (PHD2), plays a critical role in oxygen sensing and the regulation of hypoxia-inducible factor 1-alpha (HIF-1α) in human cells. Under normoxic conditions, EGLN1 hydroxylates HIF-1α, which leads to its recognition by the von Hippel-Lindau (VHL) ubiquitin ligase complex and subsequent degradation via the proteasome pathway. This process maintains low levels of HIF-1α, preventing the activation of hypoxia-responsive genes when oxygen is sufficient (Aggarwal2010EGLN1; Berra2003HIF).

EGLN1 is active in the cytoplasm and functions as a key oxygen sensor, ensuring that HIF-1α is only stabilized and activated under low oxygen conditions (hypoxia). In hypoxia, EGLN1 activity is reduced, allowing HIF-1α to accumulate and translocate to the nucleus, where it activates the transcription of genes involved in adaptive responses such as angiogenesis, erythropoiesis, and glycolysis (Mishra2014HIF1; Berra2003HIF).

EGLN1 also has a role in repressing HIF-1α transcriptional activity independent of its degradation function, suggesting a complex regulatory mechanism that modulates cellular responses to varying oxygen levels (To2005Suppression).

## Clinical Significance
Mutations and alterations in the EGLN1 gene, also known as prolyl hydroxylase domain-containing protein 2 (PHD2), have been implicated in various diseases and conditions. In the context of cancer, particularly endometrial cancers and uterine sarcomas, structural alterations and somatic mutations in EGLN1 have been identified. These mutations can lead to elevated levels of hypoxia-inducible factor 1-alpha (HIF1-a), contributing to cancer progression by affecting cell proliferation and angiogenesis (Kato2005Induction).

EGLN1 mutations are also associated with erythrocytosis, a condition characterized by an increased number of red blood cells. These mutations often result in a loss of function, disrupting the oxygen-sensing pathway and leading to elevated or inappropriately normal erythropoietin (EPO) levels (Sinnema2018Lossoffunction; Gangat2022Erythrocytosis). Specific germline mutations, such as p.Gln157His, have been linked to myeloproliferative neoplasms, suggesting a potential role in disease pathogenesis (Albiero2011Analysis).

In high-altitude environments, EGLN1 variants influence susceptibility to high-altitude pulmonary edema (HAPE) and adaptation. Certain polymorphisms and methylation patterns in EGLN1 are associated with increased risk or protection against HAPE, affecting gene expression and blood oxygen saturation levels (Sharma2022Differential; Mishra2012EGLN1).

## Interactions
EGLN1, also known as prolyl hydroxylase domain-containing protein 2 (PHD2), is involved in several protein interactions that regulate hypoxia-inducible factor (HIF) stability and activity. EGLN1 interacts with the C-terminal oxygen-dependent degradation domain (C-ODD) of HIF-1α, inhibiting its transcriptional activity independently of the von Hippel-Lindau (VHL) degradation pathway (To2005Suppression). This interaction occurs irrespective of oxygen tension, indicating that EGLN1 can bind to HIF-1α even under hypoxic conditions (To2005Suppression).

EGLN1 also interacts with other proteins, such as calreticulin, which is involved in calcium signaling and vascularization. This interaction is observed in both VHL(+) and VHL(-) renal carcinoma cells upon EGLN1 knockdown (Haffey2009iTRAQ). Additionally, EGLN1's interaction with proteins involved in chromatin-dependent RNA polymerase activity and mRNA processing, such as PARP1 and SET, suggests a role in transcriptional regulation (Haffey2009iTRAQ).

The protein's ability to bind both the NODD and CODD regions of HIF1α is attributed to its unique structural features, including a mixed surface potential that allows interaction with specific regions of HIF1α (Villar2007Identification). These interactions highlight EGLN1's role in modulating HIF activity and its potential as a target for therapeutic interventions.


## References


[1. (Mishra2014HIF1) Aastha Mishra and M. A. Qadar Pasha. HIF-1 and EGLN1 Under Hypobaric Hypoxia: Regulation of Master Regulator Paradigm, pages 81–91. Springer India, 2014. URL: http://dx.doi.org/10.1007/978-81-322-1928-6_8, doi:10.1007/978-81-322-1928-6_8. This article has 0 citations.](https://doi.org/10.1007/978-81-322-1928-6_8)

[2. (To2005Suppression) Kenneth K.W. To and L. Eric Huang. Suppression of hypoxia-inducible factor 1α (hif-1α) transcriptional activity by the hif prolyl hydroxylase egln1. Journal of Biological Chemistry, 280(45):38102–38107, November 2005. URL: http://dx.doi.org/10.1074/jbc.M504342200, doi:10.1074/jbc.m504342200. This article has 132 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.M504342200)

[3. (Gangat2022Erythrocytosis) Naseema Gangat, Jennifer L. Oliveira, Tavanna R Porter, James D. Hoyer, Aref Al-Kali, Mrinal M. Patnaik, Animesh Pardanani, and Ayalew Tefferi. Erythrocytosis associated with <i>epas1</i>(<i>hif2a</i>), <i>egln1</i>(<i>phd2</i>), <i>vhl, epor</i> or <i>bpgm</i> mutations: the mayo clinic experience. Haematologica, 107(5):1201–1204, February 2022. URL: http://dx.doi.org/10.3324/haematol.2021.280516, doi:10.3324/haematol.2021.280516. This article has 5 citations.](https://doi.org/10.3324/haematol.2021.280516)

[4. (Berra2003HIF) E. Berra. Hif prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of hif-1 in normoxia. The EMBO Journal, 22(16):4082–4090, August 2003. URL: http://dx.doi.org/10.1093/emboj/cdg392, doi:10.1093/emboj/cdg392. This article has 1062 citations.](https://doi.org/10.1093/emboj/cdg392)

[5. (Arsenault2016The) Patrick R. Arsenault, Daisheng Song, Yu Jin Chung, Tejvir S. Khurana, and Frank S. Lee. The zinc finger of prolyl hydroxylase domain protein 2 is essential for efficient hydroxylation of hypoxia-inducible factor α. Molecular and Cellular Biology, 36(18):2328–2343, September 2016. URL: http://dx.doi.org/10.1128/mcb.00090-16, doi:10.1128/mcb.00090-16. This article has 14 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1128/mcb.00090-16)

[6. (Sharma2022Differential) Kavita Sharma, Aastha Mishra, Himanshu Singh, Tashi Thinlas, and M. A. Qadar Pasha. Differential methylation in egln1 associates with blood oxygen saturation and plasma protein levels in high-altitude pulmonary edema. Clinical Epigenetics, September 2022. URL: http://dx.doi.org/10.1186/s13148-022-01338-z, doi:10.1186/s13148-022-01338-z. This article has 5 citations and is from a peer-reviewed journal.](https://doi.org/10.1186/s13148-022-01338-z)

[7. (Mishra2012EGLN1) Aastha Mishra, Ghulam Mohammad, Tashi Thinlas, and M. A. Qadar Pasha. Egln1 variants influence expression and sa<scp>o</scp>2 levels to associate with high-altitude pulmonary oedema and adaptation. Clinical Science, 124(7):479–489, December 2012. URL: http://dx.doi.org/10.1042/cs20120371, doi:10.1042/cs20120371. This article has 38 citations and is from a peer-reviewed journal.](https://doi.org/10.1042/cs20120371)

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[12. (Aggarwal2010EGLN1) Shilpi Aggarwal, Sapna Negi, Pankaj Jha, Prashant K. Singh, Tsering Stobdan, M. A. Qadar Pasha, Saurabh Ghosh, Anurag Agrawal, Bhavana Prasher, Mitali Mukerji, S. K. Brahmachari, P. P. Majumder, M. Mukerji, S. Habib, D. Dash, K. Ray, S. Bahl, L. Singh, A. Sharma, S. Roychoudhury, G. R. Chandak, K. Thangaraj, D. Parmar, S. Sengupta, D. Bharadwaj, S. K. Rath, J. Singh, G. N. Jha, K. Virdi, V. R. Rao, S. Sinha, A. Singh, A. K. Mitra, S. K. Mishra, Q. Pasha, S. Sivasubbu, R. Pandey, A. Baral, P. K. Singh, A. Sharma, J. Kumar, T. Stobdan, Y. Bhasin, C. Chauhan, A. Hussain, E. Sundaramoorthy, S. P. Singh, A. Bandyopadhyay, K. Dasgupta, A. K. Reddy, C. J. Spurgeon, M. M. Idris, V. Khanna, A. Dhawan, M. Anand, R. Shankar, R. S. Bharti, M. Singh, A. P. Singh, A. J. Khan, P. P. Shah, A. B. Pant, R. Kaur, K. K. Bisht, A. Kumar, V. Rajamanickam, E. Wilson, A. Thangadurai, P. K. Jha, M. Maulik, N. Makhija, A. Rahim, S. Sharma, R. Chopra, P. Rana, M. Chidambaram, A. Maitra, R. Chawla, S. Soni, P. Khurana, M. N. Khan, S. D. Sutar, A. Tuteja, K. Narayansamy, R. Shukla, S. Prakash, S. Mahurkar, K. Radha Mani, J. Hemavathi, S. Bhaskar, P. Khanna, G. S. Ramalakshmi, S. M. Tripathi, N. Thakur, B. Ghosh, R. Kukreti, T. Madan, R. Verma, G. Sudheer, A. Mahajan, S. Chavali, R. Tabassum, S. Grover, M. Gupta, J. Batra, A. Kumar, A. Nejatizadeh, M. Vaid, S. K. Das, S. Sharma, M. Sharma, R. Chatterjee, J. A. Paul, P. Srivastava, C. Rajput, U. Mittal, M. Singh, M. Hariharan, S. Das, K. Chaudhuri, M. Sengupta, M. Acharya, A. Bhattacharyya, A. Saha, A. Biswas, M. Chaki, A. Gupta, S. Mukherjee, S. Mookherjee, I. Chattopadhyay, T. Banerjee, M. Chakravorty, C. Misra, G. Monadal, S. Sengupta, De. D. Dutta, S. Bajaj, I. Deb, A. Banerjee, R. Chowdhury, D. Banerjee, D. Kumar, S. R. Das, S. Tiwari, A. Bharadwaj, S. Khanna, I. Ahmed, S. Parveen, N. Singh, D. Dasgupta, S. S. Bisht, R. Rajput, B. Ghosh, N. Kumar, A. Chaurasia, J. K. Abraham, A. Sinha, V. Scaria, T. P. Sethi, A. K. Mandal, and A. Mukhopadhyay. Egln1 involvement in high-altitude adaptation revealed through genetic analysis of extreme constitution types defined in ayurveda. Proceedings of the National Academy of Sciences, 107(44):18961–18966, October 2010. URL: http://dx.doi.org/10.1073/pnas.1006108107, doi:10.1073/pnas.1006108107. This article has 121 citations.](https://doi.org/10.1073/pnas.1006108107)

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