Abstract
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.
References
Bernstein, N.K., Cherney, M.M., Loetscher, H., Ridley, R.G., and James, M.N.G. (1999). Crystal structure of the novel aspartic proteinase zymogen proplasmepsin II from P. falciparum. Nat. Struct. Biol.6, 32–37.Search in Google Scholar
Brik, A. and Wong, C.-H. (2003). HIV-1 protease: mechanism and drug discovery. Org. Biomol. Chem.1, 5–14.10.1039/b208248aSearch in Google Scholar
Dunn, B.M. (2002). Structure and mechanism of the pepsin-like family of aspartic peptidases. Chem. Rev.102, 4431–4458.10.1021/cr010167qSearch in Google Scholar
Green, T., Ganesh, O., Perry, K., Smith, L., Phylip, L.H., Logan, T.M., Hagen, S.J., Dunn, B.M., and Edison, A.S. (2004). IA3, an aspartic proteinase inhibitor from Saccharomyces cerevisiae, is intrinsically unstructured in solution. Biochemistry43, 4071–4081.10.1021/bi034823nSearch in Google Scholar
Gribouval, O., Gonzales, M., Neuhaus, T., Aziza, J., Bieth, E., Laurent, N., Bouton, J.M., Feuillet, F., Makni, S., Amar, H.B., et al. (2005). Mutations in genes in the renin-angiotensin system are associated with autosomal recessive renal tubular dysgenesis. Nat. Genet.37, 964–968.10.1038/ng1623Search in Google Scholar
Khan, A.R. and James, M.N.G. (1998). Molecular mechanisms for the conversion of zymogens to active proteolytic enzymes. Protein Sci.7, 815–836.10.1002/pro.5560070401Search in Google Scholar
Lee, A.Y., Gulnik, S.V., and Erickson, J.W. (1998). Conformational switching in an aspartic proteinase. Nat. Struct. Biol.5, 866–870.10.1038/2306Search in Google Scholar
Li, M., Phylip, L.H., Lees, W.E., Winther, J.R., Dunn, B.M., Wlodawer, A., Kay, J., and Gustchina, A. (2000). The aspartic proteinase from Saccharomyces cerevisiae folds its own inhibitor into a helix. Nat. Struct. Biol.7, 113–117.Search in Google Scholar
Moore, S.A., Sielecki, A.R., Chernaia, M.M., Tarasova, N.I., and James, M.N.G. (1995). Crystal and molecular structures of human progastricsin at 1.62 Å resolution. J. Mol. Biol.247, 466–485.Search in Google Scholar
Ng, K.K.S., Petersen, J.F.W., Cherney, M.M., Garen, C., Zalatoris, J.J., Rao-Naik, C., Dunn, B.M., Martzen, M.R., Peanasky, R.J., and James, M.N.G. (2000). Structural basis for the inhibition of porcine pepsin by Ascaris pepsin inhibitor-3. Nat. Struct. Biol.7, 653–657.10.1038/77950Search in Google Scholar
Oefner, C., Binggeli, A., Breu, V., Bur, D., Clozel, J.-P., D'Arcy, A., Dorn, A., Fischli, W., Gruninger, F., Guller, R., et al. (1999). Renin inhibition by substituted piperidines: a novel paradigm for the inhibition of monomeric aspartic proteinases? Chem. Biol.6, 127–131.10.1016/S1074-5521(99)89004-8Search in Google Scholar
Phylip, L.H., Lees, W.E., Brownsey, B.G., Bur, D., Dunn, B.M., Winther, J.R., Gustchina, A., Li, M., Copeland, T., Wlodawer, A., and Kay, J. (2001). The potency and specificity of the interaction between IA3 and its target aspartic proteinase. J. Biol. Chem.276, 2023–2030.10.1074/jbc.M008520200Search in Google Scholar PubMed
ten Have, A., Dekkers, E., Kay, J., Phylip, L.H., and van Kan, J.A.L. (2004). An aspartic proteinase gene family in the filamentous fungus Botrytis cinerea contains members with novel features. Microbiology150, 2475–2489.Search in Google Scholar
Tigue, N.J. and Kay, J. (1998). Autoprocessing and peptide substrates for human herpesvirus 6 proteinase. J. Biol. Chem.273, 26441–26446.10.1074/jbc.273.41.26441Search in Google Scholar PubMed
Wood, J.M., Maibaum, J., Rahuel, J., Grutter, M.G., Cohen, N-C., Rasetti, V., Ruger, H., Goschke, R., Stutz, S., Fuhrer, W., et al. (2003). Structure-based design of aliskiren, a novel orally effective renin inhibitor. Biochem. Biophys. Res. Commun.308, 698–705.10.1016/S0006-291X(03)01451-7Search in Google Scholar
©2006 by Walter de Gruyter Berlin New York
