A systems biological analysis of apoptosome formation and apoptosis execution supports allosteric procaspase-9 activation.

The protease caspase-9 is activated on the apoptosome, a multi-protein signal transduction platform that assembles in response to mitochondria-dependent apoptosis initiation. Despite extensive molecular research, the assembly of the holo-apoptosome and the process of caspase-9 activation remain incompletely understood. Here we therefore integrated quantitative data on the molecular interactions and proteolytic processes during apoptosome formation and apoptosis execution, and conducted mathematical simulations to investigate the resulting biochemical signalling, quantitatively and kinetically.

Interestingly, when implementing the homo-dimerisation of procaspase-9 as a prerequisite for activation, the calculated kinetics of apoptosis execution and the efficacy of caspase-3 activation failed to replicate experimental data. In contrast, assuming a scenario in which procaspase-9 is activated allosterically upon binding to the apoptosome backbone, the mathematical simulations quantitatively and kinetically reproduced all experimental data. These data included a XIAP threshold concentration at which apoptosis execution is suppressed in HeLa cervical cancer cells, half-times of procaspase-9 processing, as well as the molecular timer function of the apoptosome.

Our study therefore provides novel mechanistic insight into apoptosome-dependent apoptosis execution and suggests that caspase-9 is activated allosterically by binding to the apoptosome backbone. Our findings challenge the currently prevailing dogma that all initiator procaspases require homo-dimerisation for activation.

J Biol Chem. 2014 Aug 8. pii: jbc.M114.590034. [Epub ahead of print]

A systems biological analysis of apoptosome formation and apoptosis execution supports allosteric procaspase-9 activation.

Würstle ML(1), Rehm M(2).

Author information:

(1)Royal College of Surgeons in Ireland, Ireland.

(2)Royal College of Surgeons in Ireland, Ireland mrehm@rcsi.ie

“Abeta oligomers and brain inflammation link synapse failure to neuronal insulin resistance and depression in Alzheimer’s disease”

The Centre for Systems Medicine is delighted to announce another speaker to its 2015 seminar series: 

  Prof. Sergio T. Ferreira.

Professor of Biophysics,Biochemistry, and Neuroscience,

Institute of Biophysics Carlos Chagas Filho & Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio
de Janeiro

 Venue: Albert Lecture Theatre, RCSI, 9am Friday 27th February 2015

Lecture entitled: ‘”Abetaoligomers and brain inflammation link synapse failure to neuronal insulinresistance and depression in Alzheimer’s disease”

Prof. Ferreira has  over  15 years extensive experience in investigating molecular and cellular mechanisms leading to synapse failure and memory loss in Alzheimer’s disease.His main research focus has been on understanding intracellular signaling pathways disrupted or altered when neurons are exposed to Ab oligomers, both in vitro and in vivo.
With particular interest in mechanisms leading to mood alterations in AD and in
shared mechanisms of pathogenesis between AD and diabetes. http://www2.bioqmed.ufrj.br/ldn/sergio.html

All very welcome to attend,

Prof. Jochen Prehn

World Cancer Day Today, 4th February 2015

Cancer Research – Past, Present and Future. Leading Irish and International scientists discuss how cancer research and treatment has evolved in recent years, and what the future holds.

https://www.youtube.com/watch?v=iSi2EO4zyQo&feature=youtu.be

Systems Medicine symposium, BREAST-PREDICT,Irish Cancer
Society Collaborative Cancer Research Centre marking World Cancer Day, 4th February 2015.