Mathematical Model of UPR (What is UPR (is a cellular stress response…
Mathematical Model of UPR
What is UPR
is a cellular stress response related to the endoplasmic reticulum (ER) stress.
Controls Protein folding in ER.
Overactivation of UPR is associated with Prion diseases and neurodegenerative diseases:
Inhibition of UPR could be a potential treatment for these diseases.
It is also involved in other diseases:
type II diabetes
amyotrophic lateral sclerosis (ALS), glomerulonephritis
acute kidney injury
Protein folding and quality control:
disulfide bond formation
On mammalian ER membrane there exists three well-known sensors for unmitigated unfolded protein accumulation:
Each of these proteins signal a response
aiding protein folding and removing unfolded proteins
In silico: "performed on computer or via computer simulation"
ODE "ordinary differential equations": is a differential equation containing one or more functions of one independent variable and the derivatives of those functions.
Model of UPR
"The model comprises four main modules interconnected to each other."
“translation attenuation module”
which is associated with PERK, describes the control of translation and the apoptotic signals.
“adaptive response modules”
IRE1 α and ATF6 branches, which together control XBP1 dynamics and BiP synthesis.
The IRE1 α branch
The ATF6 branch
“receptor activation module”
which describes the dynamics of all the three membrane receptors, IRE1 α, PERK and ATF6, with regards to the unfolded protein (UFP) accumulation.
There are 3 hypothesis for this model
For IRE1 in Yeasts: BiP binds to IRE1 monomers and prevents them from activation (no need for direct involvement of UFP)
UFP binds directly to IRE1 and facilitates the activation (no need for direct involvement of BiP)
both BiP and UFP are involved in the activation
unmitigated ER stress
where the response mechanisms such as chaperone-assisted protein folding and ER-associated degradation (ERAD) are ineffective in reducing the amount or the rate of accumulation of UFP in the ER.
IRE1 a complex
is formed of 4 monomers, and each quadromer has 2 catalytic domains.
Each active domain catalyses the unconventional splicing of the XBP1 mRNA, which in turn translates into a transcription factor enhancing BiP synthesis.
The ATF6 branch is connected to the IRE1 α branch through the regulation of XBP1 and BiP mRNA