# SERPINC1

## Overview
The SERPINC1 gene encodes the protein serpin family C member 1, commonly known as antithrombin, which is a serine protease inhibitor playing a critical role in the regulation of blood coagulation. Antithrombin functions by inhibiting several key enzymes in the coagulation cascade, thereby preventing excessive clot formation and maintaining hemostatic balance (Ruf2024SERPINC1; Mulder2017SERPINC1). This protein is categorized as a glycoprotein and is primarily synthesized in the liver before being secreted into the bloodstream. The activity of antithrombin is significantly enhanced in the presence of heparin, which accelerates its anticoagulant effects (Lu2017SerpinC1Antithrombin). Beyond its anticoagulant properties, antithrombin also exhibits anti-inflammatory functions, further underscoring its importance in physiological processes (Lu2017SerpinC1Antithrombin). Mutations in the SERPINC1 gene can lead to antithrombin deficiency, a condition associated with an increased risk of thrombotic events (Mulder2017SERPINC1; Wang2023Identification).

## Structure
The SERPINC1 gene encodes antithrombin, a serine protease inhibitor crucial for regulating blood coagulation. The primary structure of antithrombin consists of a single polypeptide chain of 432 amino acids, following the cleavage of a 32 amino acid signal peptide (Zhang2020Novel). The secondary structure includes three β-folds (A-C) and nine α-helices (A-I), along with a reactive center loop (RCL) (Wang2023Identification). The tertiary structure features a heparin-binding site encoded by portions of exons 2 and 3, and a C-terminal region encoded by exon 6 (Wang2023Identification). 

Antithrombin's quaternary structure can involve dimer formation, although this is not its primary functional form (GarridoRodríguez2024Analysis). Post-translational modifications, such as disulfide bond formation and N-glycosylation, are essential for the protein's proper folding and function (Wang2023Identification). These modifications occur in the endoplasmic reticulum, directed by the signal peptide (Wang2023Identification). Mutations in SERPINC1 can lead to structural changes that affect the protein's stability and function, such as the disruption of disulfide bonds or truncation of critical domains (Zhang2020Novel; Wang2023Identification).

## Function
The SERPINC1 gene encodes antithrombin, a serine protease inhibitor crucial for regulating blood coagulation. In healthy human cells, antithrombin functions by inhibiting several key enzymes in the coagulation cascade, including thrombin and factors IXa, Xa, XIa, and XIIa, thereby preventing excessive clot formation (Ruf2024SERPINC1; Mulder2017SERPINC1). Antithrombin is a single-chain glycoprotein secreted by hepatocytes into the bloodstream, where it plays a vital role in maintaining hemostatic balance (Ruf2024SERPINC1).

The activity of antithrombin is significantly enhanced in the presence of heparin, a glycosaminoglycan, which accelerates the formation of irreversible complexes between antithrombin and clotting factors, thus enhancing its anticoagulant effect (Lu2017SerpinC1Antithrombin). This interaction is facilitated by the heparin-binding site at the N-terminus of the antithrombin protein (Ruf2024SERPINC1).

Beyond its role in coagulation, antithrombin also exhibits anti-inflammatory properties. It can inhibit thrombin-induced inflammatory pathways and other proinflammatory coagulation enzymes, such as factor Xa, which are involved in the production of interleukins and other inflammatory molecules (Lu2017SerpinC1Antithrombin). These functions highlight the importance of antithrombin in both coagulation and inflammation regulation.

## Clinical Significance
Mutations in the SERPINC1 gene, which encodes the antithrombin protein, are primarily associated with antithrombin deficiency, a condition that significantly increases the risk of venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism (Mulder2017SERPINC1; Wang2023Identification). This deficiency can be classified into two types: Type I, characterized by a quantitative defect due to haplo-insufficiency, and Type II, a qualitative defect involving normal levels of dysfunctional protein (Polyak2020New). 

The condition is rare, affecting approximately 1 in 2000-3000 individuals, and is often inherited in an autosomal dominant manner (Polyak2020New). Mutations in SERPINC1 can lead to both quantitative and qualitative deficiencies, with over 400 pathogenic mutations identified, including point mutations, splice site variants, and small insertions/deletions (Mulder2017SERPINC1; Wang2023Identification). 

In addition to VTE, SERPINC1 mutations have been linked to arterial thrombotic events, such as ischemic stroke, particularly when combined with antithrombin deficiency (Kim2022Utility). Regulatory mutations affecting vitamin D response elements in SERPINC1 can also exacerbate the effects of vitamin D deficiency, potentially increasing thrombosis risk (Toderici2016Identification).

## Interactions
SERPINC1, which encodes antithrombin, is involved in various protein interactions that influence its function in coagulation and cancer biology. In the context of nasopharyngeal carcinoma (NPC), SERPINC1 interacts with proteins involved in apoptosis and cell cycle regulation. Its knockdown in NPC cells leads to increased apoptosis and reduced proliferation, associated with changes in apoptosis-related proteins such as Bax, Bcl-2, and survivin, and cell cycle proteins like cyclin D1 and p53 (Xu2019Knockdown).

In hepatocellular carcinoma (HCC), SERPINC1 acts as a tumor suppressor by inducing apoptosis and inhibiting macrophage M2 polarization through the ubiquitin-proteasome system. It affects the ubiquitination of proteins like HIF1A and HMGB1, which are involved in apoptosis and immune response pathways (Xu2021Serpinc1).

SERPINC1 also interacts with protein disulfide isomerase PDIA4, which is crucial for its secretion. Knockdown of PDIA4 significantly reduces SERPINC1 secretion, highlighting its role in maintaining protein stability and secretion efficiency (Samoudi2020In).

In lung cancer, SERPINC1 overexpression is linked to increased cell migration, invasion, and proliferation, with changes in the expression of metastasis-related proteins and activation of the PI3K/AKT pathway (Zhang2022Synergistic).


## References


[1. (Zhang2020Novel) Fuyong Zhang, Ying Gui, Yu Lu, Denghe Liu, Huaping Chen, Xue Qin, and Shan Li. Novel serpinc1 missense mutation (cys462tyr) causes disruption of the 279cys-462cys disulfide bond and leads to type ⅰ hereditary antithrombin deficiency. Clinical Biochemistry, 85:38–42, November 2020. URL: http://dx.doi.org/10.1016/j.clinbiochem.2020.07.004, doi:10.1016/j.clinbiochem.2020.07.004. This article has 5 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.clinbiochem.2020.07.004)

[2. (Mulder2017SERPINC1) René Mulder, F. Nanne Croles, André B. Mulder, James A. Huntington, Karina Meijer, and Michaël V. Lukens. <scp>serpinc</scp>1 gene mutations in antithrombin deficiency. British Journal of Haematology, 178(2):279–285, March 2017. URL: http://dx.doi.org/10.1111/bjh.14658, doi:10.1111/bjh.14658. This article has 33 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1111/bjh.14658)

[3. (Xu2019Knockdown) Jin Xu, Yin Ying, Gaoyun Xiong, Liqin Lai, Qingliang Wang, and Yue Yang. Knockdown of serpin peptidase inhibitor clade c member�1 inhibits the growth of nasopharyngeal carcinoma cells. Molecular Medicine Reports, March 2019. URL: http://dx.doi.org/10.3892/mmr.2019.10021, doi:10.3892/mmr.2019.10021. This article has 4 citations and is from a peer-reviewed journal.](https://doi.org/10.3892/mmr.2019.10021)

[4. (Xu2021Serpinc1) Dacai Xu, Jiawen Wu, Liang Dong, Wenwen Luo, Lanying Li, Daolin Tang, and Jinbao Liu. Serpinc1 acts as a tumor suppressor in hepatocellular carcinoma through inducing apoptosis and blocking macrophage polarization in an ubiquitin-proteasome manner. Frontiers in Oncology, November 2021. URL: http://dx.doi.org/10.3389/fonc.2021.738607, doi:10.3389/fonc.2021.738607. This article has 13 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fonc.2021.738607)

[5. (Zhang2022Synergistic) Jun Zhang, Zhijia Tang, Xi Guo, Yunxia Wang, Yuhong Zhou, and Weimin Cai. Synergistic effects of nab-ptx and anti-pd-1 antibody combination against lung cancer by regulating the pi3k/akt pathway through the serpinc1 gene. Frontiers in Oncology, August 2022. URL: http://dx.doi.org/10.3389/fonc.2022.933646, doi:10.3389/fonc.2022.933646. This article has 6 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fonc.2022.933646)

[6. (Ruf2024SERPINC1) Maximilian Ruf, Sarah Cunningham, Alexandra Wandersee, Regine Brox, Susanne Achenbach, Julian Strobel, Holger Hackstein, and Sabine Schneider. Serpinc1 c.1247dupc: a novel serpinc1 gene mutation associated with familial thrombosis results in a secretion defect and quantitative antithrombin deficiency. Thrombosis Journal, February 2024. URL: http://dx.doi.org/10.1186/s12959-024-00589-5, doi:10.1186/s12959-024-00589-5. This article has 0 citations and is from a peer-reviewed journal.](https://doi.org/10.1186/s12959-024-00589-5)

[7. (Kim2022Utility) Seondeuk Kim, Woo-Jin Lee, Jangsup Moon, and Keun-Hwa Jung. Utility of the serpinc1 gene test in ischemic stroke patients with antithrombin deficiency. Frontiers in Neurology, June 2022. URL: http://dx.doi.org/10.3389/fneur.2022.841934, doi:10.3389/fneur.2022.841934. This article has 2 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fneur.2022.841934)

[8. (Lu2017SerpinC1Antithrombin) Zeyuan Lu, Feng Wang, and Mingyu Liang. Serpinc1/antithrombin iii in kidney-related diseases. Clinical Science, 131(9):823–831, April 2017. URL: http://dx.doi.org/10.1042/cs20160669, doi:10.1042/cs20160669. This article has 52 citations and is from a peer-reviewed journal.](https://doi.org/10.1042/cs20160669)

[9. (Toderici2016Identification) Mara Toderici, María Eugenia de la Morena-Barrio, José Padilla, Antonia Miñano, Ana Isabel Antón, Juan Antonio Iniesta, María Teresa Herranz, Nuria Fernández, Vicente Vicente, and Javier Corral. Identification of regulatory mutations in serpinc1 affecting vitamin d response elements associated with antithrombin deficiency. PLOS ONE, 11(3):e0152159, March 2016. URL: http://dx.doi.org/10.1371/journal.pone.0152159, doi:10.1371/journal.pone.0152159. This article has 7 citations and is from a peer-reviewed journal.](https://doi.org/10.1371/journal.pone.0152159)

[10. (Samoudi2020In) Mojtaba Samoudi, Chih‐Chung Kuo, Caressa M. Robinson, Km Shams‐Ud‐Doha, Song‐Min Schinn, Stefan Kol, Linus Weiss, Sara Petersen Bjorn, Bjorn G. Voldborg, Alexandre Rosa Campos, and Nathan E. Lewis. In situ detection of protein interactions for recombinant therapeutic enzymes. Biotechnology and Bioengineering, 118(2):890–904, November 2020. URL: http://dx.doi.org/10.1002/bit.27621, doi:10.1002/bit.27621. This article has 1 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1002/bit.27621)

[11. (GarridoRodríguez2024Analysis) Pedro Garrido-Rodríguez, Miguel Carmena-Bargueño, María Eugenia de la Morena-Barrio, Carlos Bravo-Pérez, Belén de la Morena-Barrio, Rosa Cifuentes-Riquelme, María Luisa Lozano, Horacio Pérez-Sánchez, and Javier Corral. Analysis of alphafold and molecular dynamics structure predictions of mutations in serpins. PLOS ONE, 19(7):e0304451, July 2024. URL: http://dx.doi.org/10.1371/journal.pone.0304451, doi:10.1371/journal.pone.0304451. This article has 0 citations and is from a peer-reviewed journal.](https://doi.org/10.1371/journal.pone.0304451)

[12. (Wang2023Identification) Han-lu Wang, Dan-dan Ruan, Min Wu, Yuan-yuan Ji, Xing-xing Hu, Qiu-yan Wu, Yan-ping Zhang, Bin Lin, Ya-nan Hu, Hang Wang, Yi Tang, Zhu-ting Fang, Jie-wei Luo, Li-sheng Liao, and Mei-zhu Gao. Identification and characterization of two serpinc1 mutations causing congenital antithrombin deficiency. Thrombosis Journal, January 2023. URL: http://dx.doi.org/10.1186/s12959-022-00443-6, doi:10.1186/s12959-022-00443-6. This article has 8 citations and is from a peer-reviewed journal.](https://doi.org/10.1186/s12959-022-00443-6)

[13. (Polyak2020New) Margarita E. Polyak and Elena V. Zaklyazminskaya. New genetic variant in the serpinc1 gene: hereditary antithrombin deficiency case report, familial thrombosis and considerations on genetic counseling. BMC Medical Genetics, April 2020. URL: http://dx.doi.org/10.1186/s12881-020-01001-5, doi:10.1186/s12881-020-01001-5. This article has 5 citations and is from a peer-reviewed journal.](https://doi.org/10.1186/s12881-020-01001-5)