Adaptation of the behaviour of an aspartic proteinase inhibitor by relocation of a lysine residue by one helical turn.
In addition to self-inhibition of aspartic proteinase zymogens by their intrinsic proparts, the activity of certain members of this enzyme family can be modulated through active-site occupation by extrinsic polypeptides such as the small IA3 protein from Saccharomyces cerevisiae. The unprecedented mechanism by which IA3 helicates to inhibit its sole target aspartic proteinase locates an i, i+4 pair of charged residues (Lys18+Asp22) on an otherwise-hydrophobic face of the amphipathic helix. The nature of these residues is not crucial for effective inhibition, but re-location of the lysine residue by one turn (+4 residues) in the helical IA3 positions its side chain in the mutant IA3-proteinase complex in an orientation essentially identical to that of the key lysine residue in zymogen proparts. The binding of the extrinsic mutant IA3 shows pH dependence reminiscent of that required for the release of intrinsic zymogen proparts so that activation can occur.
Winterburn
Tim J
TJ
School of Biosciences, Cardiff University, Cardiff CF10 3US, Wales, UK.
Wyatt
David M
DM
Phylip
Lowri H
LH
Berry
Colin
C
Bur
Daniel
D
Kay
John
J
D000222:Adaptation, Physiological / Q000502:physiology*; D001224:Aspartic Acid / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006863:Hydrogen-Ion Concentration; D008239:Lysine / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship
D011480:Protease Inhibitors; D001224:Aspartic Acid; D016282:Aspartic Acid Endopeptidases; D008239:Lysine