Title : C1 inhibitor serpin domain structure reveals the likely mechanism of heparin potentiation and conformational disease
Abstract :
- C1 inhibitor, a member of the serpin family, is a major down-regulator of inflammatory processes in blood
- Genetic deficiency of C1 inhibitor results in hereditary angioedema, a dominantly inheritable, potentially lethal disease
- Here we report the first crystal structure of the serpin domain of human C1 inhibitor, representing a previously unreported latent form, which explains functional consequences of several naturally occurring mutations, two of which are discussed in detail
- The presented structure displays a novel conformation with a seven-stranded beta-sheet A
- The unique conformation of the C-terminal six residues suggests its potential role as a barrier in the active-latent transition
- On the basis of surface charge pattern, heparin affinity measurements, and docking of a heparin disaccharide , a heparin binding site is proposed in the contact area of the serpin-proteinase encounter complex
- We show how polyanions change the activity of the C1 inhibitor by a novel "sandwich" mechanism, explaining earlier reaction kinetic and mutagenesis studies
- These results may help to improve therapeutic C1 inhibitor preparations used in the treatment of hereditary angioedema, organ transplant rejection, and heart attack