TY - JOUR
T1 - Propeptides of eukaryotic proteases encode histidines to exploit organelle pH for regulation
AU - Elferich, Johannes
AU - Williamson, Danielle M.
AU - Krishnamoorthy, Bala
AU - Shinde, Ujwal
PY - 2013/8
Y1 - 2013/8
N2 - 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.
AB - 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.
KW - Cathepsins
KW - Secretory pathway
UR - http://www.scopus.com/inward/record.url?scp=84881141173&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84881141173&partnerID=8YFLogxK
U2 - 10.1096/fj.12-226886
DO - 10.1096/fj.12-226886
M3 - Article
C2 - 23585398
AN - SCOPUS:84881141173
SN - 0892-6638
VL - 27
SP - 2939
EP - 2945
JO - FASEB Journal
JF - FASEB Journal
IS - 8
ER -