Journal
BIOCHEMISTRY
Volume 41, Issue 45, Pages 13444-13450Publisher
AMER CHEMICAL SOC
DOI: 10.1021/bi026494p
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- NCI NIH HHS [R01 CA81102] Funding Source: Medline
- NIGMS NIH HHS [R01 GM57300] Funding Source: Medline
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Elongation factor-2 kinase (eEF-2K) is a Ca2+/calmodulin-dependent protein kinase that phosphorylates and inactivates eEF-2 and that can regulate the rate of protein synthesis at the elongation stage. Here we report that a slight decrease in pH, within the range observed in vivo, leads to a dramatic activation of eEF-2K. The activity of eEF-2K in mouse liver extracts, as well as the activity of purified recombinant human eEF-2K, is low at pH 7.2-7.4 and is increased by severalfold when the pH drops to 6.6-6.8. eEF-2K requires calmodulin for activity at neutral as well as acidic pH. Kinetic studies demonstrate that the pH does not affect the K-M for ATP or eEF-2 and activation of eEF-2K at acidic pH is due to an increase in V-max. To analyze the potential role of eEF-2K in regulating protein synthesis by pH, we constructed a mouse fibroblast cell line that expresses eEF-2K in a tetracycline-regulated manner. Overexpression of eEF-2K led to a decreased rate of protein synthesis at acidic pH, but not at neutral pH. Our results suggest that pH-dependent activation of eEF-2K may play a role in the global inhibition of protein synthesis during tissue acidosis, which accompanies such processes as hypoxia and ischemia.
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