Serpin - Mutations That Result in Spontaneous Formation of Latent (or Latent-like), Inactive Conformations

Mutations That Result in Spontaneous Formation of Latent (or Latent-like), Inactive Conformations

Certain pathogenic mutations in serpins can promote inappropriate transition to the monomeric latent state (see figure 8a for the structure of the latent state). This causes disease because it reduces the amount of active inhibitory serpin. For example, the disease-linked antithrombin variants wibble and wobble, both promote formation of the latent state.

It is also worth highlighting a structure of a disease-linked human antichymotrypsin variant that further demonstrates the extraordinary flexibility of the serpin scaffold. The structure of antichymotrypsin (Leucine 55 to Proline) revealed a novel "δ" conformation that may represent an intermediate between the native and latent state (Figure 12). In the delta conformation, four residues of the RCL are inserted into the top of β-sheet A. The bottom half of the sheet is filled as a result of one of the α-helices (the F-helix) partially switching to a β-strand conformation, completing the β-sheet hydrogen bonding. It is unclear whether other serpins can adopt this conformer, and whether this conformation has a functional role. However, it is speculated that the δ-conformation may be adopted by Thyroxine-binding globulin during thyroxine release.