Download SnapShot: Time Scales in Cell Biology

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SnapShot: Time Scales in Cell Biology
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Maya Shamir,1 Yinon Bar-On,1 Rob Phillips,2 and Ron Milo1
Weizmann Institute of Science, Rehovot, Israel; 2 California Institute of Technology, Pasadena, CA, USA
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Please send comments to [email protected]
Characteristic rates and durations in cell biology
Model bacterium (E. coli)
vs.
Mammalian cell line (HeLa)
diffusion limited
on-rate
10 7-10 9 M-1 s-1
ligand induced
conformational change
1 ms
passage across
membrane
channel
μs
endocytosis
1 min
diffusion over 10 μm
1-10 s
transporter
ms
molecular motor
1 μm/s
DNA replication
103 nt/s
diffusion over 1 μm
10-100 ms
DNA replication
10 3 nt/min
cell movement - 1 μm/min
cell movement - 10 μm/s
transcription
cell cycle
1 hr
10-100 nt/s
10-100 nt/s
1 min/gene [1 kbp]
10 min/gene [10 kbp]
translation
10 aa/s
1 min/protein [300 aa]
flagellar rotation
100 Hz
cell cycle
1 day
10 aa/s
1 min/protein [300 aa]
protein folding
ms-s
half-life
metabolite
mRNA
protein
1s
10 min
1 hr
1 min
10 hr
1 day
Orders of magnitude in time scales
neurotransmitter
[please send
diffusion across synapse suggestion]
10-6
(µs)
fastest enzyme
turnover time
ATP synthase
rotation
protein
folding
10-3
(ms)
allosteric
average enzyme
conformational
turnover time
change in proteins
10 0
gene
splicing
budding yeast
generation time
10 3
(s)
10 6
(≈20 min)
endocytosis
minimal bacterial
generation time
taste bud cell
lifetime
(≈2 weeks)
circadian
clock
red blood cell
lifetime
Characteristic time scales extracted from the literature for exponentially growing E. coli and HeLa cells at 37 °C. Numbers should only serve
as “rule of thumb” values. For example, the half-lives of metabolites (turnover time of the metabolite pool) span over 3 orders of magnitude.
Some processes are shown only in one of the cell types yet are relevant to both.
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Cell no. , Text text text
SnapShot: Time Scales in Cell Biology
Maya Shamir,1 Yinon Bar-On,1 Rob Phillips,2 and Ron Milo1
Weizmann Institute of Science, Rehovot, Israel; 2 California Institute of Technology, Pasadena, CA, USA
1
Please send comments to [email protected]
How to get a protein across a neuron on time?
In order for a protein to get from the tip of the axon to the cell soma in a 1
cm long neuron, two main mechanisms are possible. Getting there by
diffusion (D≈10 μm2 /s) would take over a week (scaling like R 2 /D).
Alternatively, a molecular motor with a speed of 1 μm/s will transport the
protein in just over an hour. In neurons over a meter long, say in a human or
a giraffe, even molecular motors are predicted to take many days, and
mechanisms such as local axonal translation may assist cells with
overcoming this challenge.
How long does it take to get a functional GFP molecule?
Consider an inducible GFP system in E. coli - from the moment an inducer
is added to the medium, it activates a cellular response by diffusing into the
cell or binding to a receptor within a second. Transcription and translation
take on the order of a minute, with protein folding occurring concurrently.
However, a maturation process which involves cyclization and oxidation of
the chromophore is essential for producing fluorescence, and takes tens of
minutes in the originally developed fluorophores. Evolved versions of GFP
reduce the maturation time to a few minutes, so the whole process from
induction of expression to a fluorescent signal is achieved within minutes.
Can metabolism wait for gene expression?
Metabolic networks and gene regulatory networks are the epicenter of
biological regulation. Interestingly, the time scales at which these networks
exert their control are quite distinct. The characteristic pool size
(concentration) of a metabolite in central metabolism is on the order of 1
mM, while the flux of reactions in the cellular metabolic highway of
glycolysis is usually on the order of 1 mM/s in bacteria and 0.1-0.01 mM/s in
mammalian cell lines as inferred from glucose uptake rates. Thus, the
turnover time is on the order of a second for bacteria and a minute in
mammalian cell lines, as befitting their relative growth rates. This means that
if the production and consumption reactions are not in balance, the
metabolite pool will be consumed (or compounded) before the central
dogma can do anything about it. Regulating metabolic enzymes by means
of gene expression is not feasible as the average time scale for such
regulation takes minutes. This calls for a faster regulation mechanism, such
as allosteric regulation and post-translational modifications, which can
respond on the same time scale as turnover times in metabolism.
A speed limit on crawling cells?
Motility of many cells is powered by actin polymerization at the leading edge
of the lamellipodium. The speed limit for a growing actin network is the
growth rate of a single filament oriented perpendicular to the leading edge
of the lamellipodium. The on-rate for the the addition of an actin monomer
to the growing tip is 10 7-10 8 M-1 s-1. The reported cellular concentration of
actin monomers ranges between 1-100 µM, and in such cases we choose
to use the geometrical mean (10 µM). Each polymerized actin monomer
adds 3 nm to the filament, and we thus get a velocity on the order of 1 μm/s
(3x107 M-1s-1x 10 µM x 3 nm) which is observed for example for Listeria and
similar cells. The observed crawling speed of keratocytes (in charge of
wound healing) and fibroblasts are one and two orders of magnitude slower,
respectively. The counteracting membrane tension and the fact that a
lamellipodium is not a single actin filament, but an ensemble of filaments,
are some of the mechanisms that can further reduce the speed of cells.
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Are mammalian cells a slow-motion version of bacterial cells?
Mammalian cells and bacteria work under similar physical and chemical
constraints. For example, the diffusion coefficients and the rates of the RNA
polymerase and ribosomes are quite similar. Yet, with a larger cell size and
gene length, the functional time scales in a mammalian cell are extended.
For example, diffusion of a protein across a cell will take ~10 s in a 10 μm
mammalian cell and ~0.1 s in a 1 μm bacterial cell. Similarly, even though
transcription rates are comparable, an average bacterial gene is 1 kbp long,
and thus will take about a minute to transcribe, while an average mammalian
gene is 10 kbp long, and thus its transcription will take about 10 minutes.
The same reasoning also holds true for additional cellular processes, such
as the turnover times of metabolites. We find that what is true for a bacteria
on a one second time scale is true for the mammalian cell (and probably also
for an elephant) on a one minute time scale. We can thus half jokingly think
of a mammalian cell as a slow motion version of a bacterium.
How fast can Olympic athletes respond to the starter’s pistol in a
100-meter dash?
Upon hearing the pistol shot, athletes must process and propagate an
electric impulse from the brain all the way to their feet to activate the
muscles (≈1 meter). Considering the speed of the action potential (10-100
m/s), this implies a latency of 10-100 ms regardless of other time-consuming
processes, such as the speed of sound and signal processing in the brain.
Indeed, the best athletes respond after ≈120 ms, and a reaction time below
100 ms is immediately disqualified as a false start, according to the Olympic
rules from the International Association of Athletics Federations.
What is the lifetime of different cells in our body?
How do different cell types compare with the lab cell lines that divide once a
day? The intestine epithelium turns over in less than a week, our skin
epidermis in a week to a month, and tastebuds in about two weeks, enabling
us to regain the joys of taste even after a tongue burn. Red blood cells are
famous for having a characteristic lifetime of 4 months, a fact that allows us
to donate 0.5 L from our 5 L of blood every 3 months without depleting our
red blood cell pool. A striking difference exists between sperm cells and
oocytes, with a lifetime of ≈50 days and ≈50 years, respectively. Our fat cells
and skeleton replace themselves in about 10 years, while most of the
neurons in the central nervous system, and our eye lens cells do not replace
at all. In principle, could the body replace all of its tissues on a one day
time-scale? Replacement requires, for example, polymerization of the
proteins which is one of the most energy intensive processes in the cell. 4
ATP equivalents are required per amino acid (MW≈110 Da), with a glucose
molecule (MW=180 Da) giving ≈30 ATPs. The adult body has about 10 kg
protein which to be polymerized will require consuming more than 2 kg
glucose (4 ATP/30 ATP x 180 Da/110 Da x 10 kg) - much higher than the daily
body energy budget, thus demonstrating why the human body cannot
compete with the proliferation of lab cell lines.
ACKNOWLEDGMENTS
We thank Uri Moran, Nigel Orme, Ulrich Schwarz, Alex Sigal, Avigdor Eldar,
Sasha Bershadsky, Eran Bouchbinder, Ori Avinoam, Arren Bar-Even, Rotem
Sorek, Danny Ben-Zvi, Eitan Bibi, Dan Tawfik, Ayelet Erez,... and the
Weizmann students of “Cell Biology by the Numbers” course 2015-16 for
help in preparing this SnapShot.
REFERENCES
Alon, U. (2006). An Introduction to Systems Biology: Design Principles of Biological Circuits (New York: Chapman & Hall/CRC).
Milo, R., and Phillips, R. (2016). Cell Biology by the Numbers (New York: Garland Science).
Milo, R., Jorgensen, P., Moran, U., Weber, G., and Springer, M. (2010). BioNumbers – the database of key numbers in molecular and cell biology. Nucleic Acids
Res. 38, D750–D753.
Neidhardt, F.C., Ingraham, J.L., and Schaechter, M. (1990). Physiology of the Bacterial Cell: A Molecular Approach (Sunderland, MA: Sinauer Associates).
Phillips, R., Kondev, J., and Theriot, J. (2008). Physical Biology of the Cell (London: Garland Science).
Weinstein, L. (2012). Guesstimation 2.0: Solving Today’s Problems on the Back of a Napkin (Princeton, NJ: Princeton University Press).
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