Serine Protease inhibitors (
Serpins) like
antithrombin, antitrypsin,
neuroserpin, antichymotrypsin,
protein C-inhibitor and
plasminogen activator inhibitor is involved in important
biological functions like blood coagulation, fibrinolysis,
inflammation, cell migration and complement activation.
Serpins native state is metastable, which undergoes transformation to a more stable state during the process of
protease inhibition.
Serpins are prone to conformation defects, however little is known about the factors and mechanisms which promote its conformational change and misfolding. Helix B region in
serpins is with several point mutations which result in pathological conditions due to polymerization. Helix B analysis for residue burial and cavity was undertaken to understand its role in
serpin structure function. A structural overlap and an accessible surface area analysis showed the deformation of strand 6B and exposure of helix B at N-terminal end in cleaved conformation but not in the native and latent conformation of various inhibitory
serpins. A cleaved
polymer like conformation of antitrypsin also showed deformation of s6B and helix B exposure. Cavity analysis showed that helix B residues were part of the largest cavity in most of the
serpins in the native state which increase in size during the transformation to cleaved and latent states. These data for the first time show the importance of strand 6B deformation and exposure of helix B in smooth insertion of the reactive center loop during
serpin inhibition and indicate that helix B exposure due to variants may increase its
polymer propensity.
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