Mathematical Modeling Reveals the Importance of the DED Filament Composition in the Effects of Small Molecules Targeting Caspase-8/c-FLIPL Heterodimer.

Biochemistry. Biokhimii︠a︡
Nikita V Ivanisenko, Inna N Lavrik

Abstract

Procaspase-8 activation at the death-inducing signaling complex (DISC) triggers extrinsic apoptotic pathway. Procaspase-8 activation takes place in the death effector domain (DED) filaments and is regulated by c-FLIP proteins, in particular, by the long isoform c-FLIPL. Recently, the first-in-class chemical probe targeting the caspase-8/c-FLIPL heterodimer was reported. This rationally designed small molecule, FLIPin, enhances caspase-8 activity after initial heterodimer processing. Here, we used a kinetic mathematical model to gain an insight into the mechanisms of FLIPin action in a complex with DISC, in particular, to unravel the effects of FLIPin at different stoichiometry and composition of the DED filament. Analysis of this model has identified the optimal c-FLIPL to procaspase-8 ratios in different cellular landscapes favoring the activity of FLIPin. We predicted that the activity FLIPin is regulated via different mechanisms upon c-FLIPL downregulation or upregulation. Our study demonstrates that a combination of mathematical modeling with system pharmacology allows development of more efficient therapeutic approaches and prediction of optimal treatment strategies.

References

Sep 7, 2002·The Journal of Biological Chemistry·Olivier MicheauMarkus G Grütter
Mar 26, 2003·Cell Death and Differentiation·I LavrikS Kirchhoff
Jun 24, 2004·The Biochemical Journal·Kelly M BoatrightGuy S Salvesen
Sep 15, 2004·The Journal of Cell Biology·M BenteleR Eils
Feb 11, 2005·The Journal of Biological Chemistry·Alexander GolksInna N Lavrik
Sep 24, 2005·Cell Death and Differentiation·A GolksI N Lavrik
Jun 26, 2007·Nature Reviews. Immunology·Peter H KrammerInna N Lavrik
Apr 14, 2009·Nature·Sabrina L SpencerPeter K Sorger
May 7, 2009·Proceedings of the National Academy of Sciences of the United States of America·Jong W YuYigong Shi
Mar 10, 2010·Molecular Systems Biology·Leo NeumannRoland Eils
Aug 11, 2010·The Journal of Cell Biology·Nicolai FrickerInna N Lavrik
Mar 19, 2011·Cell·Sabrina L Spencer, Peter K Sorger
Nov 15, 2011·Cell Death and Differentiation·I N Lavrik, P H Krammer
Nov 24, 2011·Molecular Systems Biology·Bree B AldridgePeter K Sorger
Feb 9, 2012·Experimental Cell Research·Selcen OztürkInna N Lavrik
Dec 21, 2012·Expert Opinion on Therapeutic Targets·Simone Fulda
Jun 28, 2013·Cell Communication and Signaling : CCS·Kolja Schleich, Inna N Lavrik
May 31, 2014·Cell Death & Disease·I N Lavrik
Oct 18, 2014·Cellular and Molecular Life Sciences : CMLS·Alexey V ZamaraevInna N Lavrik
Apr 30, 2015·Trends in Cell Biology·Deborah A Flusberg, Peter K Sorger
Sep 27, 2018·PLoS Computational Biology·Jörn H BuchbinderInna N Lavrik
Jan 22, 2020·Cell Death and Differentiation·Laura K HillertInna N Lavrik

❮ Previous
Next ❯

Software Mentioned

SciPy package

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.