benefits of translation regulation in the unfolded protein
J.B. Axelsen and
(A mathematical model for the dynamics
of translation regulation)
The model deals with the
dynamics of having a stock of passive mRNA (m) for
rapid conversion to active mRNA (m*).
(1) The moment the cell experiences a shock in the form of
vastly increased levels of unfolded proteins (U),
the folding chaperone (BiP) is released from a
complex with an endonuclease (Ire1p). This
endonuclease then (2) cleaves passive mRNA
into (3) active mRNA, which then opens for
parallel production (4) of a signalling
protein (Hac1p) which then initiates transcription
(5) of the folding chaperone (BiP).
The chaperone brings the unfolded protein levels down, and the
loop is closed.
In the paper we analyse the
model and discuss the relevant parameters for making this system
work. We found that there exists a relation between degradation
times for the mRNAs (tm,t*) and the rate with which Ire1p
converts passive to active mRNA (c): c~1/tm <<
The degradation time for the
passive mRNA should match the conversion rate because otherwise
sensitivity is lost (This can be realised from the steady state
condition). The short lifetime of m* is necessary
for an overshooting effect of the concentration of Hac1p.
The overshooting will bring BiP faster to its
required level, since the change in BiP is a direct
function of Hac1p.
Parameters derived from both
in vivo and in vitro experiments shows that the
relation above holds. However, as discussed in the paper, by
varying the model parameters we found that the model is most
sensitive to t*, which lead to a
reinterpretation of raw data in order to match the peak times of
measured mRNA for Hac1p. This is perfectly in line
with the philosophy of the model which states that t*
This model is the first of its
kind, since the demands on biological information is quite high
and the system is novel in its design. Especially the
transmembrane kinase/endonuclease Ire1p is a
remarkable feat of evolution. The system is also present in
mammals in a sligthly modified form.