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Article

N-Glycosylation as a Tool to Study Antithrombin Secretion, Conformation, and Function

1
Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia Campus Mare Nostrum, IMIB-Arrixaca, 30008 Murcia, Spain
2
Institute of Biophysics (IBF), National Research Council of Italy (CNR), 153–90146 Palermo, Italy
3
Grupo de investigación CB15/00055 del Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII) Madrid, 28029 Madrid, Spain
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(2), 516; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020516
Received: 29 October 2020 / Revised: 31 December 2020 / Accepted: 31 December 2020 / Published: 6 January 2021
(This article belongs to the Collection Protein Folding)
N-linked glycosylation is a crucial post-translational modification involved in protein folding, function, and clearance. N-linked glycosylation is also used therapeutically to enhance the half-lives of many proteins. Antithrombin, a serpin with four potential N-glycosylation sites, plays a pivotal role in hemostasis, wherein its deficiency significantly increases thrombotic risk. In this study, we used the introduction of N-glycosylation sites as a tool to explore what effect this glycosylation has on the protein folding, secretion, and function of this key anticoagulant. To accomplish this task, we introduced an additional N-glycosylation sequence in each strand. Interestingly, all regions that likely fold rapidly or were surrounded by lysines were not glycosylated even though an N-glycosylation sequon was present. The new sequon in the strands of the A- and B-sheets reduced secretion, and the B-sheet was more sensitive to these changes. However, the mutations in the strands of the C-sheet allowed correct folding and secretion, which resulted in functional variants. Therefore, our study revealed crucial regions for antithrombin secretion and could potentially apply to all serpins. These results could also help us understand the functional effects of natural variants causing type-I deficiencies. View Full-Text
Keywords: Glycosylation; folding; antithrombin; serpin; coagulation; thrombosis; bioengineering Glycosylation; folding; antithrombin; serpin; coagulation; thrombosis; bioengineering
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MDPI and ACS Style

Águila, S.; Noto, R.; Luengo-Gil, G.; Espín, S.; Bohdan, N.; de la Morena-Barrio, M.E.; Peñas, J.; Rodenas, M.C.; Vicente, V.; Corral, J.; Manno, M.; Martínez-Martínez, I. N-Glycosylation as a Tool to Study Antithrombin Secretion, Conformation, and Function. Int. J. Mol. Sci. 2021, 22, 516. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020516

AMA Style

Águila S, Noto R, Luengo-Gil G, Espín S, Bohdan N, de la Morena-Barrio ME, Peñas J, Rodenas MC, Vicente V, Corral J, Manno M, Martínez-Martínez I. N-Glycosylation as a Tool to Study Antithrombin Secretion, Conformation, and Function. International Journal of Molecular Sciences. 2021; 22(2):516. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020516

Chicago/Turabian Style

Águila, Sonia, Rosina Noto, Ginés Luengo-Gil, Salvador Espín, Nataliya Bohdan, María E. de la Morena-Barrio, Julia Peñas, Maria C. Rodenas, Vicente Vicente, Javier Corral, Mauro Manno, and Irene Martínez-Martínez. 2021. "N-Glycosylation as a Tool to Study Antithrombin Secretion, Conformation, and Function" International Journal of Molecular Sciences 22, no. 2: 516. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020516

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