Bcl-xL deamidation is regulated by multiple ion transporters and is intramolecularly catalyzed

So Hee Dho, Scott R. Manson, Sung Hee Jung, Jae Cheong Lim, Steven J. Weintraub

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)995-1001
Number of pages7
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1865
Issue number7
DOIs
StatePublished - Jul 2018

Keywords

  • Bcl-x
  • Deamidation
  • Histidine
  • NHE

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