# N-glycosylation in the SERPIN domain of the C1-esterase inhibitor in hereditary angioedema

## TL;DR

The study explores how N-glycosylation in the SERPIN domain of C1-esterase inhibitor affects its function and contributes to hereditary angioedema.

## Contribution

The study identifies specific N-glycosylation sites in C1-INH that are critical for protein function and pathogenesis of hereditary angioedema.

## Key findings

- Deleting N at the three natural N-linked sequons (N238, N253, and N352) causes pathologic consequences.
- Substituting N with A at these sites disrupts sugar attachment but preserves protein expression and function.
- An additional N-linked sugar at N272 impairs C1-INH function.

## 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 4 sets consisting of 26 variants at or near the N-linked sequon (NXS/T). Among these, 6 are reported in patients with hereditary angioedema and 5 are known C1-INH variants without accessible clinical histories. We systematically evaluated their expression, structure, and functional activity with C1s̄, FXIIa, and kallikrein. Our findings showed that of the 11 reported variants, 7 were deleterious. Deleting N at the 3 naturally occurring N-linked sequons (N238, N253, and N352) resulted in pathologic consequences. Altering these sites by substituting N with A disrupted N-linked sugar attachment, but preserved protein expression and function. Furthermore, an additional N-linked sugar generated at N272 impaired 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-INH is critical in assisting protein folding and function. Altering/deleting N-linked sugar at the glycosylation sites leads to pathologic consequences.