N-glycans and the N terminus of protein C inhibitor affect the cofactor-enhanced rates of thrombin inhibition
(2008) In Journal of Biological Chemistry 283(27). p.18601-18611- Abstract
- Protein C inhibitor (PCI) is a serine protease inhibitor, displaying broad protease specificity, found in blood and other tissues. In blood, it is capable of inhibiting both procoagulant and anticoagulant proteases. Mechanisms that provide specificity to PCI remain largely unrevealed. In this study we have for the first time provided a full explanation for the marked size heterogeneity of blood-derived PCI and identified functional differences between naturally occurring PCI variants. The heterogeneity was caused by differences in N-glycan structures, N-glycosylation occupancy, and the presence of a Delta 6-N-cleaved form. Bi-, tri-, and tetra-antennary complex N-glycans were identified. Fucose residues were identified both on the core... (More)
- Protein C inhibitor (PCI) is a serine protease inhibitor, displaying broad protease specificity, found in blood and other tissues. In blood, it is capable of inhibiting both procoagulant and anticoagulant proteases. Mechanisms that provide specificity to PCI remain largely unrevealed. In this study we have for the first time provided a full explanation for the marked size heterogeneity of blood-derived PCI and identified functional differences between naturally occurring PCI variants. The heterogeneity was caused by differences in N-glycan structures, N-glycosylation occupancy, and the presence of a Delta 6-N-cleaved form. Bi-, tri-, and tetra-antennary complex N-glycans were identified. Fucose residues were identified both on the core GlcNAc and as parts of sialyl-Le(a/x) epitopes. Moreover, a glycan with a composition that implied a di-sialyl antenna was observed. PCI was N-glycosylated at all three potential N-glycosylation sites, Asn-230, Asn-243, and Asn-319, but a small fraction of PCI lacked the N-glycan at Asn-243. The overall removal of N-glycans affected the maximal heparin- and thrombomodulin-enhanced rates of thrombin inhibition differently in different solution conditions. In contrast, the Delta 6-N-region increased both the heparin- and the thrombomodulin-enhanced rates of thrombin inhibition at all conditions examined. These results thus demonstrate that the N-linked glycans and the N-terminal region of blood-derived PCI in different ways affect the cofactor-enhanced rates of thrombin inhibition and provide information on the mechanisms by which this may be achieved. The findings are medically important, in view of the documented association of PCI with atherosclerotic plaques and the promising effect of PCI on reducing hypercoagulability states. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1186859
- author
- Sun, Wei ; Parry, Simon ; Panico, Maria ; Morris, Howard R ; Kjellberg, Margareta LU ; Engström, Åke ; Dell, Anne and Schedin-Weiss, Sophia
- organization
- publishing date
- 2008
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Biological Chemistry
- volume
- 283
- issue
- 27
- pages
- 18601 - 18611
- publisher
- American Society for Biochemistry and Molecular Biology
- external identifiers
-
- wos:000257165600016
- scopus:49649093374
- ISSN
- 1083-351X
- DOI
- 10.1074/jbc.M800608200
- language
- English
- LU publication?
- yes
- id
- 87b41240-1633-45e5-85de-c5254bd8bb1b (old id 1186859)
- date added to LUP
- 2016-04-01 11:52:47
- date last changed
- 2022-01-26 19:37:10
@article{87b41240-1633-45e5-85de-c5254bd8bb1b,
abstract = {{Protein C inhibitor (PCI) is a serine protease inhibitor, displaying broad protease specificity, found in blood and other tissues. In blood, it is capable of inhibiting both procoagulant and anticoagulant proteases. Mechanisms that provide specificity to PCI remain largely unrevealed. In this study we have for the first time provided a full explanation for the marked size heterogeneity of blood-derived PCI and identified functional differences between naturally occurring PCI variants. The heterogeneity was caused by differences in N-glycan structures, N-glycosylation occupancy, and the presence of a Delta 6-N-cleaved form. Bi-, tri-, and tetra-antennary complex N-glycans were identified. Fucose residues were identified both on the core GlcNAc and as parts of sialyl-Le(a/x) epitopes. Moreover, a glycan with a composition that implied a di-sialyl antenna was observed. PCI was N-glycosylated at all three potential N-glycosylation sites, Asn-230, Asn-243, and Asn-319, but a small fraction of PCI lacked the N-glycan at Asn-243. The overall removal of N-glycans affected the maximal heparin- and thrombomodulin-enhanced rates of thrombin inhibition differently in different solution conditions. In contrast, the Delta 6-N-region increased both the heparin- and the thrombomodulin-enhanced rates of thrombin inhibition at all conditions examined. These results thus demonstrate that the N-linked glycans and the N-terminal region of blood-derived PCI in different ways affect the cofactor-enhanced rates of thrombin inhibition and provide information on the mechanisms by which this may be achieved. The findings are medically important, in view of the documented association of PCI with atherosclerotic plaques and the promising effect of PCI on reducing hypercoagulability states.}},
author = {{Sun, Wei and Parry, Simon and Panico, Maria and Morris, Howard R and Kjellberg, Margareta and Engström, Åke and Dell, Anne and Schedin-Weiss, Sophia}},
issn = {{1083-351X}},
language = {{eng}},
number = {{27}},
pages = {{18601--18611}},
publisher = {{American Society for Biochemistry and Molecular Biology}},
series = {{Journal of Biological Chemistry}},
title = {{N-glycans and the N terminus of protein C inhibitor affect the cofactor-enhanced rates of thrombin inhibition}},
url = {{http://dx.doi.org/10.1074/jbc.M800608200}},
doi = {{10.1074/jbc.M800608200}},
volume = {{283}},
year = {{2008}},
}