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(NAS Colloquium) Proteolytic Processing and Physiological Regulation (1999) / Chapter Skim
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Structural aspects of activation pathways of aspartic protease zymogens and viral 3C protease precursors
Pages 10968-10975

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From page 10968...
... This statement does not hold for the chymotrypsin-like serine proteases as the active sites of these zymogens are able to bind protein inhibitors that induce conformational changes that form the oxyanion hole in spite of the ion pair involving Asp-194 and Ile-16 being absent (11~. Proteolysis of the portion of the prosegments that interact with the active site residues is prevented in several different ways.
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From page 10969...
... are in green, those of the gastricsin portion of the zymogen are in blue except for those regions that undergo large conformational changes, Ser-1 to Ala-13, Phe-71 to Thr-81 and Tyr-125 to Ala136, which are represented in mauve. The premature junction is Leu-43pSer-1, the peptide bond cleaved intramolecularly is Phe-26p to Leu-27p.
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From page 10970...
... The trigger for initiating the conversion of the gastric aspartic protease zymogens is a drop in pH (54. At neutral pH, the structures of the zymogens are stabilized by the electrostatic interactions of the ion pairs and the inactive conformation is maintained (16~.
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From page 10971...
... falciparum revealed some surprising contrasts with the gastric aspartic protease zymogens (40~. Instead of blocking a preformed active site, as in the gastric zymogens, the prosegment in proplasmepsin causes a major distortion of the molecule, preventing the formation of a functional active site.
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From page 10972...
... It should be noted that the bond cleaved in autoactivation of proplasmepsin II, Phe-112p to Leu-113p, is located at the C terminus of the prosegment helix 2, which must be one of the early locations to lose its secondary structure upon acidification. Once the active site is formed, the scissile bond, now in an extended conformation, then can be presented for cleavage either in cis or in trans.
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From page 10973...
... Acidification may be necessary to induce the Tyr-Asp loop opening for the Gly-124p to Ser-1 scissile bond to assume an extended conformation suitable for proteolytic cleavage. Alternatively, low pH may be required if the maturase itself has an acidic pH optimum.
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From page 10974...
... The crystal structures confirmed that the picornaviral 3C proteases are structurally related to the chymotrypsin family of serine proteases. Based on some of the unique structural details, the authors of the crystal structure papers (61-63)
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From page 10975...
... (1998) in The Aspartic Proteases: Retroviral and Cellular Enzymes, ed.
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Key Terms

  • aspartic protease
  • intramolecular cleavage
  • protease zymogens
  • conformational changes
  • gastric aspartic

  • aspartic proteases
  • hydrogen bonds
  • ion pair
  • serine proteases
  • active sites

  • crystal structure
  • extended conformation
  • peptide bond
  • promature junction
  • preformed active

  • site residues
  • catalytic aspartates
  • gastric zymogens
  • human pepsin
  • psi loops

  • gene product
  • human gastricsin
  • viral polyprotein
  • conversion pathway
  • autocatalytic excision

  • chymotrypsin family
  • scissile bond
  • salt bridges
  • proteolytic activity
  • limited proteolysis


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