18 research outputs found
Propeptides of eukaryotic proteases encode histidines to exploit organelle pH for regulation
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.—Elferich, J., Williamson, D. M., Krishnamoorthy, B., Shinde, U., Propeptides of eukaryotic proteases encode histidines to exploit organelle pH for regulation. FASEB J. 27, 2939–2945 (2013). www.fasebj.or
Propeptides of eukaryotic proteases encode histidines to exploit organelle pH for regulation
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.—Elferich, J., Williamson, D. M., Krishnamoorthy, B., Shinde, U. Propeptides of eukaryotic proteases encode histidines to exploit organelle pH for regulation
Molecular structure and conformation of stereocilia tip-links elucidated by cryo-electron tomography [preprint]
Mechanosensory transduction (MT), the conversion of mechanical stimuli into electrical signals, underpins hearing and balance and is carried out within hair cells in the inner ear. Hair cells harbor actin-filled stereocilia, arranged in rows of descending heights, where the tips of stereocilia are connected to their taller neighbors by a filament composed of protocadherin 15 (PCDH15) and cadherin 23 (CDH23), deemed the ‘tip-link’. Tension exerted on the tip-link opens an ion channel at the tip of the shorter stereocilia, thus converting mechanical force into an electrical signal. While biochemical and structural studies have provided insights into the molecular composition and structure of isolated portions of the tip-link, the architecture, location and conformational states of intact tip-links, on stereocilia, remains unknown. Here we report in situ cryo-electron microscopy imaging of the tip-link in mouse stereocilia. We observe individual PCDH15 molecules at the tip and shaft of stereocilia and determine their stoichiometry, conformational heterogeneity, and their complexes with CDH23. The PCDH15/CDH23 complexes occur in clusters, frequently with more than one copy of PCDH15 at the tip of stereocilia, suggesting that tip-links might consist of more than one copy of the PCDH15/CDH23 heterotetramer and by extension, might include multiple MT complexes
Strategy for Compositional Analysis of the Hair Cell Mechanotransduction Complex Using TIRF Microscopy
BradyAJohnston/MolecularNodes: v2.9.0 for Blender 3.5+
Re-release of 2.9.0 with rebased main.
What's Changed
Overhaul Documenation
Include a MolecularNodes application template for quick start
Improve node consistency and descriptions
Full Changelog: https://github.com/BradyAJohnston/MolecularNodes/compare/v2.8.1...v2.9.
BradyAJohnston/MolecularNodes: v2.9.0 for Blender 3.5+
What's Changed:
Overhauled documentation
Improved consistency in node interfaces
Application template for quicker star
Pacritinib, a Dual FLT3/JAK2 Inhibitor, Reduces Irak-1 Signaling in Acute Myeloid Leukemia
BradyAJohnston/MolecularNodes: v2.9.1 for Blender 3.5+
Clean up some unnecessary files which seems to maybe fix #30