Selective inhibition of cotranslational translocation of vascular cell adhesion molecule 1
| Autor: | Berndt Oberhauser, Hanna Harant, Christiane Dascher-Nadel, Katharina Marquardt, Erwin P. Schreiner, Ivan J. D. Lindley, Shirley Wang, Jan E. de Vries, Carolyn A. Foster, Jürgen Besemer |
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| Rok vydání: | 2005 |
| Předmět: |
Signal peptide
Cell signaling Molecular Sequence Data Vascular Cell Adhesion Molecule-1 Chromosomal translocation Protein Sorting Signals Biology Endoplasmic Reticulum Transfection Peptides Cyclic Sensitivity and Specificity Cell Line Substrate Specificity Animals Humans Amino Acid Sequence Sequence Deletion Multidisciplinary Dose-Response Relationship Drug Cell adhesion molecule Endoplasmic reticulum Membrane Proteins Translocon Cell biology Protein Transport Cytosol Membrane protein Protein Biosynthesis Protein Processing Post-Translational SEC Translocation Channels Peptide Hydrolases |
| Zdroj: | Nature. 436:290-293 |
| ISSN: | 1476-4687 0028-0836 |
| Popis: | Increased expression of vascular cell adhesion molecule 1 (VCAM1) is associated with a variety of chronic inflammatory conditions, making its expression and function a target for therapeutic intervention1,2,3. We have recently identified CAM741, a derivative of a fungus-derived cyclopeptolide that acts as a selective inhibitor of VCAM1 synthesis in endothelial cells. Here we show that the compound represses the biosynthesis of VCAM1 in cells by blocking the process of cotranslational translocation, which is dependent on the signal peptide of VCAM1. CAM741 does not inhibit targeting of the VCAM1 nascent chains to the translocon channel but prevents translocation to the luminal side of the endoplasmic reticulum (ER), through a process that involves the translocon component Sec61β. Consequently, the VCAM1 precursor protein is synthesized towards the cytosolic compartment of the cells, where it is degraded. Our results indicate that the inhibition of cotranslational translocation with low-molecular-mass compounds, using specificity conferred by signal peptides, can modulate the biosynthesis of certain secreted and/or membrane proteins. In addition, they highlight cotranslational translocation at the ER membrane as a potential target for drug discovery. |
| Databáze: | OpenAIRE |
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