Apoptosis is a cell death program that is executed by the caspases, a family of cysteine proteases that typically cleave after aspartate residues during a proteolytic cascade that systematically dismantles the dying cell. Extensive signaling crosstalk occurs between caspase-mediated proteolysis and kinase-mediated phosphorylation, enabling integration of signals from multiple pathways into the decision to commit to apoptosis. A new study from Maluch et al. examines how phosphorylation within caspase cleavage sites impacts the efficiency of substrate cleavage. The results demonstrate that while phosphorylation in close proximity to the scissile bond is generally inhibitory, it does not necessarily abrogate substrate cleavage, but instead attenuates the rate. In some cases, this inhibition can be overcome by additional favorable substrate features. These findings suggest potential nuanced physiological roles for phosphorylation of caspase substrates with exciting implications for targeting caspases with chemical probes and therapeutics.
-
Cover Image
Cover Image
In blood, angiotensinogen is found in either the oxidised or reduced form, with elevated levels of the oxidised form found in several hypertensive conditions. Molecular dynamics simulations predict that the disulfide bond present in the oxidised form, shown here as glowing orange spheres, constrains the movements of the neighbouring A2 helix and the CD loop, but also leads to increased conformational sampling of the N-terminus. We observe a difference in antibody binding affinity for the N-terminus between the two redox forms of angiotensinogen which is consistent with this prediction and could be used in a diagnostic setting to assess the progression of hypertensive disorders, such as pre-eclampsia. For more, see the article by Crowther and colleagues (pp. 3319–3330). Image created by Biovidera, courtesy of Ashley Buckle and Benjamin Porebski.
Kinases leave their mark on caspase substrates
