التفاصيل البيبلوغرافية
| العنوان: |
Substrate specificity of the TIM22 mitochondrial import pathway revealed with small molecule inhibitor of protein translocation. |
| المؤلفون: |
Hasson, Samuel A., Damoiseaux, Robert, Glavin, Jenny D., Dabir, Deepa V., Walker, Scott S., Koehler, Carla M. |
| المصدر: |
Proceedings of the National Academy of Sciences of the United States of America; 5/25/2010, Vol. 107 Issue 21, p9578-9583, 6p |
| مصطلحات موضوعية: |
MEMBRANE proteins, MITOCHONDRIAL membranes, MOLECULAR chaperones, CARRIER proteins, ADENINE nucleotides, MITOCHONDRIA, CHROMOSOMAL translocation, BIOCHEMICAL genetics |
| مستخلص: |
The TIM22 protein import pathway mediates the import of membrane proteins into the mitochondrial inner membrane and consists of two intermembrane space chaperone complexes, the Tim9-Tim10 and Tim8-Tim13 complexes. To facilitate mechanistic studies, we developed a chemical-genetic approach to identify small molecule agonists that caused lethality to a tim10-1 yeast mutant at the permissive temperature. One molecule, MitoBloCK-1, attenuated the import of the carrier proteins including the ADP/ATP and phosphate carriers, but riot proteins that used the T1M23 or the Mia40/ Erv1 translocation pathways. MitoBloCK-1 impeded binding of the Tim9-Tim10 complex to the substrate during an early stage of translocation, when the substrate was crossing the outer membrane. As a probe to determine the substrate specificity of the small Tim proteins, MitoBloCK-1 impaired the import of Tim22 and Tafazzin, but not Tim23, indicating that the Tim9-Tim10 complex mediates the import of a subset of inner membrane proteins. MitoBloCK-1 also inhibited growth of mammalian cells and import of the ADP/ATP carrier, but not T1M23 substrates, confirming that MitoBloCK-1 can be used to understand mammalian mitochondrial import and dysfunction linked to inherited human disease. Our approach of screening chemical libraries for compounds causing synthetic genetic lethality to identify inhibitors of mitochondrial protein translocation in yeast validates the generation of new probes to facilitate mechanistic studies in yeast and mammalian mitochondria. [ABSTRACT FROM AUTHOR] |
|
Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) |
| قاعدة البيانات: |
Complementary Index |
Full Text Finder