Propeptides of eukaryotic proteases encode histidines to exploit organelle pH for regulation

Johannes Elferich, Danielle M. Williamson, Bala Krishnamoorthy, Ujwal Shinde

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Eukaryotic cells maintain strict control over protein secretion, in part by using the pH gradient maintained within their secretory pathway. How eukaryotic proteins evolved from prokaryotic orthologs to exploit the pH gradient for biological functions remains a fundamental question in cell biology. Our laboratory previously demonstrated that protein domains located within precursor proteins, propeptides, encode histidine-driven pH sensors to regulate organelle-specific activation of the eukaryotic proteases furin and proprotein convertase-1/3. Similar findings have been reported in other unrelated protease families. By analyzing >10,000 unique proteases within evolutionarily unrelated families, we show that eukaryotic propeptides are enriched in histidines compared with prokaryotic orthologs. On this basis, we hypothesize that eukaryotic proteins evolved to enrich histidines within their propeptides to exploit the tightly controlled pH gradient of the secretory pathway, thereby regulating activation within specific organelles. Enrichment of histidines in propeptides may therefore be used to predict the presence of pH sensors in other proteases or even protease substrates.

Original languageEnglish (US)
Pages (from-to)2939-2945
Number of pages7
JournalFASEB Journal
Volume27
Issue number8
DOIs
StatePublished - Aug 2013

Fingerprint

Histidine
Organelles
Peptide Hydrolases
Proton-Motive Force
pH sensors
Secretory Pathway
Proteins
Proprotein Convertase 1
Chemical activation
Cytology
Furin
Protein Precursors
Eukaryotic Cells
Cell Biology
Substrates

Keywords

  • Cathepsins
  • Secretory pathway

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology
  • Medicine(all)

Cite this

Propeptides of eukaryotic proteases encode histidines to exploit organelle pH for regulation. / Elferich, Johannes; Williamson, Danielle M.; Krishnamoorthy, Bala; Shinde, Ujwal.

In: FASEB Journal, Vol. 27, No. 8, 08.2013, p. 2939-2945.

Research output: Contribution to journalArticle

Elferich, Johannes ; Williamson, Danielle M. ; Krishnamoorthy, Bala ; Shinde, Ujwal. / Propeptides of eukaryotic proteases encode histidines to exploit organelle pH for regulation. In: FASEB Journal. 2013 ; Vol. 27, No. 8. pp. 2939-2945.
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