| First Author | Dho SH | Year | 2018 |
| Journal | Biochim Biophys Acta Mol Cell Res | Volume | 1865 |
| Issue | 7 | Pages | 995-1001 |
| PubMed ID | 29694915 | Mgi Jnum | J:266668 |
| Mgi Id | MGI:6199919 | Doi | 10.1016/j.bbamcr.2018.04.009 |
| Citation | Dho SH, et al. (2018) Bcl-xL deamidation is regulated by multiple ion transporters and is intramolecularly catalyzed. Biochim Biophys Acta Mol Cell Res 1865(7):995-1001 |
| abstractText | 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. |
