FC0018
IA3 polypeptide  -  Aspartic acid proteinase

Biological function
Aspartic acid proteinases are involved in a series of pathological processes and their protein inhibitors are uncommon.

Domain organization/sequence features
IA3 inhibitor is 68 residue long and its N terminal half is responsible for the inhibitory activity.

Structural evidence
Upon binding of IA3 to the proteinase, only residues 1-32 get ordered and form a helix, while the rest remains to be disordered. An extended ’capping’ arrangement exists at the C-terminal end to stabilize the inhibitory helix. No electron density was observed for the side chains of any residues beyond Lys32 in the crystal structure of the K24M mutant complex or in the structure of peptide 1 complexed with proteinase A described previously and the side chain of residue 32 makes no significant contacts with the enzyme.

Biochemical evidence
The most potent inhibition (subnanomolar at pH 4.7) was measured when the IA3 sequence was extended at its C terminus beyond Lys32.

Mechanism category
conformational selection

Significance
The fuzzy tail appears to promote α-helix formation upon binding, which establishes direct contacts with the proteinase. It might also contribute to binding via transient interactions, as well.