Identification of a pH sensor in the furin propeptide that regulates enzyme activation

Sylvain F. Feliciangeli, Laurel Thomas, Gregory K. Scott, Ezhilkani Subbian, Chien Hui Hung, Sean S. Molloy, François Jean, Ujwal Shinde, Gary Thomas

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

The folding and activation of furin occur through two pH- and compartment-specific autoproteolytic steps. In the endoplasmic reticulum (ER), profurin folds under the guidance of its prodomain and undergoes an autoproteolytic excision at the consensus furin site Arg-Thr-Lys-Arg 107 ↓ generating an enzymatically masked furin-propeptide complex competent for transport to late secretory compartments. In the mildly acidic environment of the trans-Golgi network/endosomal system, the bound propeptide is cleaved at the internal site 69HRGVTKR75 ↓, unmasking active furin capable of cleaving substrates in trans. Here, by using cellular, biochemical, and modeling studies, we demonstrate that the conserved His69 is a pH sensor that regulates the compartment-specific cleavages of the propeptide. In the ER, unprotonated His69 stabilizes a solvent-accessible hydrophobic pocket necessary for autoproteolytic excision at Arg107. Profurin molecules unable to form the hydrophobic pocket, and hence, the furin-propeptide complex, are restricted to the ER by a PACS-2- and COPI-dependent mechanism. Once exposed to the acidic pH of the late secretory pathway, protonated His69 disrupts the hydrophobic pocket, resulting in exposure and cleavage of the internal cleavage site at Arg75 to unmask the enzyme. Together, our data explain the pH-regulated activation of furin and how this His-dependent regulatory mechanism is amodel for other proteins.

Original languageEnglish (US)
Pages (from-to)16108-16116
Number of pages9
JournalJournal of Biological Chemistry
Volume281
Issue number23
DOIs
StatePublished - Jun 9 2006

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Feliciangeli, S. F., Thomas, L., Scott, G. K., Subbian, E., Hung, C. H., Molloy, S. S., Jean, F., Shinde, U., & Thomas, G. (2006). Identification of a pH sensor in the furin propeptide that regulates enzyme activation. Journal of Biological Chemistry, 281(23), 16108-16116. https://doi.org/10.1074/jbc.M600760200