Biology Reference
In-Depth Information
TABLE 14.3
Proteolysis Provides Directionality to Cell Cycle Progression?
'The chemical irreversibility of proteolysis is exploited by the cell to provide directionality at critical steps of the cell cycle.' Science (1996)
'An obvious advantage of proteolysis for controlling passage through these critical points in the cell cycle is that protein degradation is an
irreversible process, ensuring that cells proceed irreversibly in one direction through the cycle.' Textbook (2004)
'Importantly, the irreversible nature of proteolysis makes it an invaluable complement to the intrinsically reversible regulation through
phosphorylation and other post-translational modifications.' Curr. Biol. (2004)
The hydrolysis of a peptide bond, (AA)
N
þ
H
2
O
If protein turnover is rapid, then protein levels can be
quickly ramped up or down, as changing circumstances
dictate, simply by disturbing the balance between synthesis
and degradation. In such cases, proteolysis is a 'dynami-
cally reversible' process.
It is equally true of protein synthesis-and-degradation as
of phosphorylation-and-dephosphorylation that the opposing
processes are thermodynamically irreversible but dynami-
cally reversible. Dynamic irreversibility
e
which is the type
of irreversibility of relevance to cell cycle transitions
e
is not
to be sought in the thermodynamic properties of individual
reactions but in the dynamic behavior of sets of coupled
reactions with feedback. Dynamic irreversibility is
a systems-level property of molecular regulatory networks
[45]
(
Figure 14.4
).
Dynamic irreversibility is intimately connected to the
bistability of chemical reaction networks. To explain the
connection, consider the simple example of a transcription
factor, e.g., E2F, that upregulates the expression of its own
gene (
Figure 14.4
A). According to the basic principles of
biochemical kinetics, we can describe the dynamic features
of this little network by a pair of ordinary differential
equations (ODEs):
dM
dt
¼
/
(AA)
N-1
þ
AA, is a thermodynamically irreversible process,
i.e., the free energy change of this chemical reaction is
negative. But, in fact, every reaction that occurs in the cell has
D
Gwere positive, then the reactionwould proceed
in the opposite direction, as dictated by the second law of
thermodynamics. Not only is protein degradation thermo-
dynamically spontaneous but so is protein synthesis, (AA)
N
þ
G
<
0. If
D
H
2
O, because the ribosome couples
this reaction to the hydrolysis of four molecules of ATP, 4
ATP
AA
(AA)
N
þ
1
þ
/
inorganic phosphate
ions). The overall reaction, polypeptide chain elongation
þ
4H
2
O
4 ADP
þ
4P
i
(P
i
¼
/
þ
ATP hydrolysis, is an irreversible reaction (
0).
In the same way, protein phosphorylation and dephos-
phorylation are both intrinsically irreversible reactions:
Protein
D
G
<
þ
ATP
Protein-P
þ
ADP
; D
G
<
0
:
/
Protein-P
þ
H
2
O
Protein
þ
P
i
; D
G
<
0
:
/
The net effect of a cycle of protein phosphorylation and
dephosphorylation is the hydrolysis of one molecule of
ATP to ADP
P
i
. This is called a 'futile' cycle. Although
futile from an energetic point of view, the cycle may be
quite functional in the information economy of the cell,
corresponding, in computer language, to flipping a bit from
0 to 1 and back to 0. ATP hydrolysis is the price the cell
must pay for an elementary information-processing oper-
ation. A cycle of protein synthesis and degradation is also
'futile' in the same respect. The only difference is that it
costs much more ATP to synthesize and then degrade a full
protein
e
but then, there is much more 'information' in
a complete protein than in a phosphorylated amino acid
side chain.
It is incorrect to maintain that post-translational modi-
fications of proteins are intrinsically reversible whereas
proteolysis is intrinsically irreversible (
Table 14.3
). The
reverse of protein degradation is protein synthesis in the
same way that the reverse of protein dephosphorylation is
protein phosphorylation
[45]
. The only differences are
'time and money': protein turnover (synthesis and degra-
dation) takes longer and costs more than post-translational
modifications. Indeed, it is common to find that protein
synthesis and degradation are dynamically balanced, so
that the total level of the protein is held at a constant value.
þ
k
sm
H
ð
P
Þ
k
dm
M
(1)
dP
dt
¼
k
sp
M
k
dp
P
where M
¼
rate constants
for synthesis and degradation of mRNA and protein, and
H(P)
[mRNA], P
¼
[protein], k
sm
etc.
¼
probability that the gene encoding the transcription
factor is being actively transcribed. Suppose that this prob-
ability
¼
1 when the transcription factor is bound to the
gene's promoter, and
¼
when not bound. Then the function
H(P) is commonly taken to be a Hill function:
H
ð
P
Þ¼
ε
¼
ε
K
p
þ
P
n
(2)
K
p
þ
P
n
where K
p
is the equilibrium dissociation constant (units
of concentration, say nM) of the transcription factor
e
promoter complex, and n is the Hill exponent, n
2or4
depending on whether the transcription factor binds to the
promoter as a homodimer or homotetramer.
¼
