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Updated: Feb 11, 2026
Examining BCL-2 Family Function with Large Unilamellar Vesicles
Published on: October 5, 2012
Bcl-xL deamidation is regulated by multiple ion transporters and is intramolecularly catalyzed
So Hee Dho1, Scott R Manson2, Sung Hee Jung3
1Radioisotope Research Division, Department of Research Reactor Utilization, Korea Atomic Energy Research Institute, Daejeon 34057, Republic of Korea; Division of Urology and The Alvin J. Siteman Cancer Center, Washington University School of Medicine, Saint Louis, MO 63110, United States.
Abstract:
In susceptible tumor cells, DNA-damaging antineoplastic agents induce an increase in intracellular pH during the premitochondrial stage of apoptosis. The rate of nonenzymatic deamidation of two asparagines in the anti-apoptotic protein Bcl-xL is accelerated by this increase in pH. Deamidation of these asparagines is a signal for the degradation of Bcl-xL, which is a component of the apoptotic response to DNA damage. It has previously been shown that the increase in pH is mediated by the ion transporter Na+/H+ exchanger 1 in some cells. Here we demonstrate that one or more additional ion transporters also have a role in the regulation of Bcl-xL deamidation in at least some tumor cell lines and fibroblasts. As a second, independent finding, we report that there are histidines in close proximity to the Bcl-xL deamidation sites that are highly conserved in land-dwelling species and we present evidence that deamidation of human Bcl-xL is intramolecularly catalyzed in a manner that is dependent upon these histidines. Further, we present evidence that these histidines act as a pH-sensitive switch that enhances the effect of the increase in pH on the rate of Bcl-xL deamidation. The conservation of such histidines implies that human Bcl-xL is in essence "designed" to be deamidated, which provides further evidence that deamidation serves as a bona fide regulatory post-translational modification of Bcl-xL.
Insights
DNA-damaging drugs trigger pH changes in cancer cells, accelerating Bcl-xL protein deamidation and degradation. This pH-mediated deamidation, influenced by ion transporters and conserved histidines, regulates apoptosis.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- DNA-damaging antineoplastic agents induce intracellular pH increase during apoptosis.
- This pH increase accelerates nonenzymatic deamidation of asparagine residues in Bcl-xL.
- Bcl-xL deamidation signals its degradation, contributing to the apoptotic response.
Purpose of the Study:
- To investigate the role of ion transporters in regulating Bcl-xL deamidation.
- To explore the mechanism of Bcl-xL deamidation, focusing on conserved histidines.
- To determine if Bcl-xL deamidation is an intramolecularly catalyzed, pH-dependent process.
Main Methods:
- Analysis of ion transporter involvement in Bcl-xL deamidation in tumor cells and fibroblasts.
- Identification and characterization of conserved histidines near Bcl-xL deamidation sites.
- Experimental evidence for intramolecular catalysis of Bcl-xL deamidation dependent on histidines.
Main Results:
- Additional ion transporters, beyond Na+/H+ exchanger 1, regulate Bcl-xL deamidation in some cell types.
- Conserved histidines near deamidation sites in Bcl-xL are crucial for the process.
- Bcl-xL deamidation is intramolecularly catalyzed and enhanced by a pH-sensitive histidine switch.
Conclusions:
- Bcl-xL deamidation is a regulated post-translational modification essential for apoptosis.
- Conserved histidines suggest an evolutionary design for pH-sensitive Bcl-xL deamidation.
- Ion transporters and specific protein residues orchestrate Bcl-xL deamidation in response to DNA damage.
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