# SERPINA12

## Overview
SERPINA12 is a gene that encodes the protein vaspin, a member of the serpin (serine protease inhibitor) family. Vaspin is primarily expressed in adipose tissue and functions as an adipokine, playing a crucial role in regulating insulin sensitivity and glucose metabolism. As a serine protease inhibitor, vaspin interacts with kallikrein-related peptidases, such as KLK7 and KLK14, to inhibit their proteolytic activity. This interaction is significant for its role in metabolic regulation, particularly in the context of obesity-related disorders. Vaspin also exhibits anti-inflammatory and anti-apoptotic properties, contributing to its protective effects against metabolic and cardiovascular diseases. The protein's structure, characterized by typical serpin features, includes a reactive center loop essential for its inhibitory function. Vaspin's interactions with glycosaminoglycans and cell-surface proteins further underscore its multifaceted role in cellular processes (Ulbricht2018Kallikreinrelated; Kurowska2021Review:; Heiker2014Vaspin).

## Structure
The SERPINA12 gene encodes the protein vaspin, a member of the serpin family, which is characterized by its role as a serine protease inhibitor. Vaspin's molecular structure includes typical serpin features such as three β-sheets and nine α-helices, forming a structural core that is crucial for its inhibitory function (Kurowska2021Review:; Heiker2014Vaspin). The reactive center loop (RCL) is a key structural element, extending from glycine 364 to proline 381, and includes a scissile bond between methionine 378 and glutamate 379, which is essential for protease specificity (Kurowska2021Review:; Heiker2014Vaspin).

Vaspin is known to undergo post-translational modifications, including glycosylation, which affects its molecular weight. The unglycosylated form of vaspin migrates at 45 kDa, with glycosylation increasing the weight by approximately 7.5 kDa (Kurowska2021Review:). Glycosylation sites are located in the N-terminus and near the RCL, but they do not impede its inhibitory activity against kallikrein 7 (Kurowska2021Review:).

The protein is remarkably thermostable, with a temperature midpoint of 70°C, indicating a robust tertiary structure (Ulbricht2015A). Vaspin also interacts with heparin, a glycosaminoglycan, through basic residues in its β-sheet A, which contributes to its activation and binding properties (Ulbricht2017Basic; Tindall2020Membrane). These structural features and interactions are critical for vaspin's biological functions and stability.

## Function
SERPINA12, also known as vaspin, is a serine protease inhibitor primarily expressed in adipose tissue. It plays a significant role in regulating insulin sensitivity and glucose metabolism. Vaspin functions as an adipokine, a type of bioactive molecule secreted by adipose tissue, and is involved in anti-inflammatory processes, potentially protecting against obesity-related metabolic disorders (Heiker2014Vaspin).

Vaspin exerts its effects by interacting with the 78 kDa glucose-regulated protein (GRP78) on the cell surface, which is recruited from the endoplasmic reticulum to the plasma membrane under conditions of ER stress. This interaction is mediated through the helical domains in the N-terminus of vaspin and transduces intracellular signaling via multiple kinase pathways, including protein kinase B (AKT) and AMP-activated kinase (PRKAA1) (Kurowska2021Review:). Vaspin has been shown to increase AKT phosphorylation in pancreatic islets and enhance endothelial nitric oxide synthase activity through Janus kinase (STAT3) activation in vascular endothelial cells (Kurowska2021Review:).

In addition to its role in glucose metabolism, vaspin inhibits the degradation of insulin by kallikrein 7, thereby increasing insulin stability and half-life (Kurowska2021Review:). It also exhibits anti-apoptotic effects, protecting vascular endothelial cells and smooth muscle cells from inflammation and apoptosis, which are relevant in the context of obesity-associated inflammation and cardiovascular disease (Heiker2014Vaspin).

## Clinical Significance
Mutations and alterations in the expression of the SERPINA12 gene, also known as vaspin, have been linked to several diseases and conditions. A significant single nucleotide polymorphism (SNP) in the SERPINA12 gene, rs77060950, is associated with higher serum vaspin levels and is linked to insulin resistance, obesity, and type 2 diabetes (Teshigawara2012Serum). This SNP affects transcriptional activity and correlates with varying serum vaspin concentrations depending on the genotype (CC, CA, AA) (Teshigawara2012Serum).

In hepatocellular carcinoma (HCC), SERPINA12 is overexpressed in tumor tissues compared to normal tissues, and its high expression is associated with poor prognosis. This suggests a potential oncogenic role for SERPINA12 in HCC, particularly in early and middle stages, and its involvement in processes like vascular invasion and immune cell infiltration (Yang2024Potential).

A rare truncating mutation, rs61757459, in the SERPINA12 gene results in a premature stop codon, leading to a truncated and unstable protein. This mutation is associated with lower circulating vaspin levels and has been studied in relation to obesity and glucose metabolism, although no significant associations with metabolic traits have been found (Breitfeld2013Analysis).

## Interactions
SERPINA12, also known as vaspin, is a serine protease inhibitor that primarily interacts with kallikrein-related peptidases, specifically KLK7 and KLK14. Vaspin forms covalent complexes with these proteases by incorporating its reactive center loop into their central β-sheet A. This interaction is crucial for its inhibitory function, particularly against KLK7, which has chymotrypsin-like specificity, and KLK14, which exhibits both trypsin- and chymotrypsin-like activities. The complex formation with KLK14 is slower compared to KLK7 (Ulbricht2018Kallikreinrelated).

Vaspin's interaction with glycosaminoglycans (GAGs), such as heparin, is also significant. It binds heparin with high affinity, which facilitates its activation and enhances its inhibition of KLK7. This binding is mediated by basic residues on β-sheet A, and mutations in these residues can decrease heparin binding and activation (Ulbricht2017Basic). Vaspin is also found bound in the extracellular matrix, suggesting that GAG interactions regulate its activity on the cell surface (Ulbricht2017Basic).

Additionally, vaspin interacts with the cell-surface GRP78/VDAC complex, which is implicated in its anti-apoptotic effects on endothelial cells (Nakatsuka2013Visceral). These interactions highlight vaspin's role in metabolic regulation and its potential therapeutic implications in obesity-related disorders.


## References


[1. (Yang2024Potential) Huan Yang, Panpan Kong, Songyu Hou, Xiaogang Dong, Imamumaimaitijiang Abula, and Dong Yan. Potential prognostic biomarker serpina12: implications for hepatocellular carcinoma. Clinical and Translational Oncology, September 2024. URL: http://dx.doi.org/10.1007/s12094-024-03689-w, doi:10.1007/s12094-024-03689-w. This article has 0 citations and is from a peer-reviewed journal.](https://doi.org/10.1007/s12094-024-03689-w)

[2. (Kurowska2021Review:) Patrycja Kurowska, Ewa Mlyczyńska, Monika Dawid, Małgorzata Jurek, Dominika Klimczyk, Joelle Dupont, and Agnieszka Rak. Review: vaspin (serpina12) expression and function in endocrine cells. Cells, 10(7):1710, July 2021. URL: http://dx.doi.org/10.3390/cells10071710, doi:10.3390/cells10071710. This article has 29 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/cells10071710)

[3. (Heiker2014Vaspin) John T. Heiker. Vaspin (serpina12) in obesity, insulin resistance, and inflammation: molecular mechanisms of vaspin function. Journal of Peptide Science, 20(5):299–306, March 2014. URL: http://dx.doi.org/10.1002/psc.2621, doi:10.1002/psc.2621. This article has 77 citations and is from a peer-reviewed journal.](https://doi.org/10.1002/psc.2621)

[4. (Tindall2020Membrane) Catherine A. Tindall, Sebastian Dommel, Veronika Riedl, David Ulbricht, Stefanie Hanke, Norbert Sträter, and John T. Heiker. Membrane phospholipids and polyphosphates as cofactors and binding molecules of serpina12 (vaspin). Molecules, 25(8):1992, April 2020. URL: http://dx.doi.org/10.3390/molecules25081992, doi:10.3390/molecules25081992. This article has 6 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/molecules25081992)

[5. (Teshigawara2012Serum) Sanae Teshigawara, Jun Wada, Kazuyuki Hida, Atsuko Nakatsuka, Jun Eguchi, Kazutoshi Murakami, Motoko Kanzaki, Kentaro Inoue, Takahiro Terami, Akihiro Katayama, Izumi Iseda, Yuichi Matsushita, Nobuyuki Miyatake, John F. McDonald, Kikuko Hotta, and Hirofumi Makino. Serum vaspin concentrations are closely related to insulin resistance, and rs77060950 atserpina12genetically defines distinct group with higher serum levels in japanese population. The Journal of Clinical Endocrinology & Metabolism, 97(7):E1202–E1207, July 2012. URL: http://dx.doi.org/10.1210/jc.2011-3297, doi:10.1210/jc.2011-3297. This article has 54 citations.](https://doi.org/10.1210/jc.2011-3297)

[6. (Ulbricht2017Basic) David Ulbricht, Kathrin Oertwig, Kristin Arnsburg, Anja Saalbach, Jan Pippel, Norbert Sträter, and John T. Heiker. Basic residues of β-sheet a contribute to heparin binding and activation of vaspin (serpin a12). Journal of Biological Chemistry, 292(3):994–1004, January 2017. URL: http://dx.doi.org/10.1074/jbc.m116.748020, doi:10.1074/jbc.m116.748020. This article has 14 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.m116.748020)

[7. (Nakatsuka2013Visceral) Atsuko Nakatsuka, Jun Wada, Izumi Iseda, Sanae Teshigawara, Kanji Higashio, Kazutoshi Murakami, Motoko Kanzaki, Kentaro Inoue, Takahiro Terami, Akihiro Katayama, Kazuyuki Hida, Jun Eguchi, Daisuke Ogawa, Yasushi Matsuki, Ryuji Hiramatsu, Hideo Yagita, Shigeru Kakuta, Yoichiro Iwakura, and Hirofumi Makino. Visceral adipose tissue-derived serine proteinase inhibitor inhibits apoptosis of endothelial cells as a ligand for the cell-surface grp78/voltage-dependent anion channel complex. Circulation Research, 112(5):771–780, March 2013. URL: http://dx.doi.org/10.1161/circresaha.111.300049, doi:10.1161/circresaha.111.300049. This article has 65 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1161/circresaha.111.300049)

[8. (Breitfeld2013Analysis) Jana Breitfeld, John T. Heiker, Yvonne Böttcher, Dorit Schleinitz, Anke Tönjes, Kerstin Weidle, Kerstin Krause, E. Bartholomeus Kuettner, Markus Scholz, Wieland Kiess, Norbert Sträter, Annette G. Beck-Sickinger, Michael Stumvoll, Antje Körner, Matthias Blüher, and Peter Kovacs. Analysis of a rare functional truncating mutation rs61757459 in vaspin (serpina12) on circulating vaspin levels. Journal of Molecular Medicine, 91(11):1285–1292, June 2013. URL: http://dx.doi.org/10.1007/s00109-013-1062-9, doi:10.1007/s00109-013-1062-9. This article has 5 citations.](https://doi.org/10.1007/s00109-013-1062-9)

[9. (Ulbricht2015A) David Ulbricht, Jan Pippel, Stephan Schultz, René Meier, Norbert Sträter, and John T. Heiker. A unique serpin p1′ glutamate and a conserved β-sheet c arginine are key residues for activity, protease recognition and stability of serpina12 (vaspin). Biochemical Journal, 470(3):357–367, September 2015. URL: http://dx.doi.org/10.1042/bj20150643, doi:10.1042/bj20150643. This article has 16 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1042/bj20150643)

[10. (Ulbricht2018Kallikreinrelated) David Ulbricht, Catherine A. Tindall, Kathrin Oertwig, Stefanie Hanke, Norbert Sträter, and John T. Heiker. Kallikrein-related peptidase 14 is the second klk protease targeted by the serpin vaspin. Biological Chemistry, 399(9):1079–1084, March 2018. URL: http://dx.doi.org/10.1515/hsz-2018-0108, doi:10.1515/hsz-2018-0108. This article has 14 citations and is from a peer-reviewed journal.](https://doi.org/10.1515/hsz-2018-0108)