The TACE zymogen: Re-examining the role of the cysteine switch

Marcos E. Milla, Patricia E. Gonzales, Jennifer D. Leonard

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

The tumor necrosis factor-α-converting enzyme (TACE) is a member of the disintegrin family of metalloproteinases (ADAMs) that plays a central role in the regulated shedding of a host of cell surface proteins. TACE is biosynthesized as a precursor protein with latent proteolytic activity (zymogen). TACE's zymogen inhibition is mediated by its Pro domain, a 197-amino acid region that serves this function as well as aiding in the secretion of this enzyme through the secretory pathway. We have discovered that a conserved "cysteine switch" consensus motif within TACE's Pro domain is, contrary to expectations, not required for maintenance of the inactive precursor state or for the secretion of this metalloproteinase in its functional form. The only role for this motif seems to be in decreasing TACE's susceptibility to proteolytic degradation during its biogenesis and maturation within the secretory pathway. Interestingly, the Pro domain of TACE seems to carry both its inhibitory and secretory functions through the same mechanism: it seems to prevent the Catalytic domain from accessing its native, functional state, resembling the function of true molecular chaperones. Recent evidence suggests that TACE may also be switched out of the active conformation even by small, drug-like molecules such as the synthetic compound SB-3CT. These findings point at the possibility of developing, in the near future, a new generation of anti-inflammatory, noncompetitive TACE inhibitors that would exert negative allosteric modulation over the activity of this key enzyme, mediating several inflammatory diseases and certain cancers.

Original languageEnglish
Pages (from-to)342-348
Number of pages7
JournalCell Biochemistry and Biophysics
Volume44
Issue number3
DOIs
StatePublished - 2006
Externally publishedYes

Keywords

  • ADAM
  • Metalloproteinase
  • Molecular chaperones
  • Tumor necrosis factor-α
  • Tumor necrosis factor-α-converting enzyme

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