N-glycosylation in the SERPIN domain of C1-Esterase Inhibitor in hereditary angioedema

Zhen Ren; John Bao; Shuangxia Zhao; Nicola Pozzi; H. Wedner; John P. Atkinson

doi:10.1172/jci.insight.185548

N-glycosylation in the SERPIN domain of C1-Esterase Inhibitor in hereditary angioedema

Zhen Ren,¹ John Bao,¹ Shuangxia Zhao,² Nicola Pozzi,³ H. Wedner,¹ and John P. Atkinson¹

Published January 17, 2025 - More info

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Abstract

Hereditary angioedema is an autosomal dominant disorder caused by defects in C1-esterase inhibitor (C1-INH), resulting in poorly controlled activation of the kallikrein-kinin system and bradykinin overproduction. C1-INH is a heavily glycosylated protein in the serine protease inhibitor (SERPIN) family, yet the role of these glycosylation sites remains unclear. To elucidate the functional impact of N-glycosylation in the SERPIN domain of C1-INH, we engineered four sets consisting of 26 variants at or near the N-linked sequon (NXS/T). Among these, six are reported in HAE patients and five are known C1-INH variants without accessible clinical histories. We systematically evaluated their expression, structure and functional activity with C1¯s, FXIIa and kallikrein. Our findings showed that of the eleven reported variants, seven are deleterious. Deleting N at the three naturally occurring N-linked sequons (N238, N253 and N352) results in pathologic consequences. Altering these sites by substituting N to A disrupts N-linked sugar attachment but preserves protein expression or function. Further, an additional N-linked sugar generated at N272 impairs C1-INH function. These findings highlight the importance of N-linked sequons in modulating the expression and function of C1-INH. Insights gained from identifying the pathological consequences of N-glycan variants should assist in defining more tailored therapy.

N-glycosylation in the SERPIN domain of C1-Esterase Inhibitor in hereditary angioedema

Zhen Ren,¹ John Bao,¹ Shuangxia Zhao,² Nicola Pozzi,³ H. Wedner,¹ and John P. Atkinson¹

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N-glycosylation in the SERPIN domain of C1-Esterase Inhibitor in hereditary angioedema

Zhen Ren,1 John Bao,1 Shuangxia Zhao,2 Nicola Pozzi,3 H. Wedner,1 and John P. Atkinson1

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Zhen Ren,¹ John Bao,¹ Shuangxia Zhao,² Nicola Pozzi,³ H. Wedner,¹ and John P. Atkinson¹