dictyNews
Electronic Edition
Volume 34, number 11
April 2, 2010
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Abstracts
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External and internal constraints to eukaryotic chemotaxis
Danny Fuller1, Wen Chen2, Micha Adler2, Alex Groisman2, Herbert
Levine2,3,
Wouter-Jan Rappel2,3, William F. Loomis1
1 Division of Biological Sciences,
2 Department of Physics
3 Center for Theoretical Biological Physics,
University of California San Diego, La Jolla, CA 92093
Proc. Natl. Acad. Sci., in press
Chemotaxis, the chemically guided movement of cells, plays an
important role
in a number of biological processes including cancer, wound healing and
embryogenesis. Chemotacting cells are able to sense shallow chemical
gradients
where the concentration of chemoattractant differs by only a few
percent from
one side of the cell to the other, over a wide range of local
concentrations.
Exactly what limits the chemotactic ability of these cells is
presently unclear.
Here we determine the chemotactic response of Dictyostelium cells to
exponential gradients of varying steepness and local concentration of
the
chemoattractant cAMP. We find that the cells are sensitive to the
steepness
of the gradient as well as to the local concentration. Using
information theory
techniques, we derive a formula for the mutual information between the
input
gradient and the spatial distribution of bound receptors and also
compute the
mutual information between the input gradient and the motility
direction in the
experiments. A comparison between these two quantities reveals that for
shallow gradients, in which the concentration difference between the
back and
the front of a 10 mm diameter cell is less than 5 %, and for small local
concentrations (less than 10 nM) the intracellular information loss
is insignificant.
Thus, external fluctuations due to the finite number of receptors
dominate and
limit the chemotactic response. For steeper gradients and higher local
concentrations, the intracellular information processing is sub-
optimal and
results in a much smaller mutual information between the input
gradient and
the motility direction than would have been predicted from the ligand-
receptor
binding process.
Submitted by Bill Loomis [[log in to unmask]]
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Self-organizing actin waves that simulate phagocytic cup structures
Günther Gerisch
PMC Biophysics 2010, 3:7
This report deals with actin waves that are spontaneously generated on
the
planar, substrate-attached surface of Dictyostelium cells. These waves
have
the following characteristics. (1) They are circular structures of
varying shape,
capable of changing the direction of propagation. (2) The waves
propagate by
treadmilling with a recovery of actin incorporation after
photobleaching of less
than 10 seconds. (3) The waves are associated with actin-binding
proteins in
an ordered 3-dimensional organization: with myosin-IB at the front and
close
to the membrane, the Arp2/3 complex throughout the wave, and coronin at
the cytoplasmic face and back of the wave. Coronin is a marker of
disassembling actin structures. (4) The waves separate two areas of
the cell
cortex that differ in actin structure and phosphoinositide composition
of the
membrane. The waves arise at the border of membrane areas rich in
phosphatidylinositol (3,4,5) trisphosphate (PIP3). The inhibition of
PIP3
synthesis reversibly inhibits wave formation. (5) The actin wave and
PIP3
patterns resemble 2-dimensional projections of phagocytic cups,
suggesting
that they are involved in the scanning of surfaces for particles to be
taken up.
PACS Codes: 87.16.Ln, 87.19.lp, 89.75.Fb
Submitted by Günther Gerisch [[log in to unmask]]
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A low-affinity ground state conformation for the dynein microtubule
binding
domain.
L. McNaughton, I. Tikhonenko, N. K. Banavali, D.M. LeMaster, and M. P.
Koonce
Wadsworth Center, Albany, NY
J. Biol. Chem, in press
Dynein interacts with microtubules through a dedicated binding domain
that
is dynamically controlled to achieve high or low affinity, depending
on the
state of nucleotide bound in a distant catalytic pocket. The active
sites
for microtubule binding and ATP hydrolysis communicate via
conformational
changes transduced through a ~10 nm length antiparallel coiled-coil
stalk,
which connects the binding domain to the roughly 300-kDa motor core.
Recently, an X-ray structure of the murine cytoplasmic dynein
microtubule
binding domain (MTBD) in a weak-affinity conformation was published,
containing a covalently constrained beta+ registry for the coiled-coil
stalk
segment (1). We here present an NMR analysis of the isolated MTBD from
Dictyostelium discoideum that demonstrates the coiled-coil beta+
registry
corresponds to the low energy conformation for this functional region of
dynein. Addition of sequence encoding roughly half of the coiled-coil
stalk
proximal to the binding tip, results in a decreased affinity of the
MTBD for
microtubules. In contrast, addition of the complete coiled-coil sequence
drives the MTBD to the conformationally unstable, high affinity
binding state.
These results suggest a thermodynamic coupling between conformational
free energy differences in the alpha and beta+ registries of the
coiled-coil
stalk that acts as a switch between high and low affinity
conformations of
the MTBD. A balancing of opposing conformations in the stalk and MTBD
enables potentially modest long-range interactions arising from ATP
binding
in the motor core to induce a relaxation of the MTBD into the stable low
affinity state.
Submitted by Michael Koonce [[log in to unmask]]
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Dictyostelium discoideum: A model system for ultrastructural analyses of
cell motility and development
M.P. Koonce and R.Gräf
Wadsworth Center, Albany, NY and Department of Cell Biology, Institute
for
Biochemistry and Biology, University of Potsdam, Germany
In press: Methods in Cell Biology.
Dictyostelium occupies an interesting niche in the grand scheme of model
organisms. On one hand, it is a compact, highly motile single cell that
presents numerous opportunities to investigate the fundamental
mechanisms
of signal transduction, cell movement, and pathogen infection.
However, upon
starvation, individual cells enter a developmental pathway that involves
cell aggregation, cell-cell adhesion, pattern formation, and
differentiation.
Thus, Dictyostelium is also well known as a basic model to study
developmental
processes. Electron microscopy (EM) has played a large role in both the
unicellular and multicellular life stages; for example, providing
image detail for
structure/function relationships of cytoskeletal proteins, the
deposition of
cellulose fibrils in maturing spores, and the identification of
intercellular
junctional complexes. Powerful combinations of robust molecular
genetic tools,
high-resolution light microscopy and EM methods make this organism an
attractive model for imaging dynamic cell processes. This methods
chapter
serves to highlight past and current EM approaches that have advanced
our
understanding of how cells and proteins function.
Submitted by Michael Koonce [[log in to unmask]]
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Genetic control of lithium sensitivity and regulation of inositol
biosynthetic
genes.
Jason King, Melanie Keim, Regina Teo, Karin E. Weening, Mridu Kapur,
Karina McQuillan, Jonathan Ryves, Ben Rogers, Emma Dalton,
Robin SB Williams and Adrian J. Harwood
PLOSone
Lithium (Li+) is a common treatment for bipolar mood disorder, a major
psychiatric illness with a lifetime prevalence of more than 1%. Risk
of bipolar
disorder is heavily influenced by genetic predisposition, but is a
complex
genetic trait and to date, genetic studies have provided little
insight into its
molecular origins. An alternative approach is to investigate the
genetics of
Li+ sensitivity. Using the social amoeba Dictyostelium, we previously
identified prolyl oligopeptidase (PO) as a modulator of Li+
sensitivity. In a
link to the clinic, PO enzyme activity is altered in bipolar disorder
patients.
Further studies demonstrated that PO is a negative regulator of
inositol(1,4,5)trisphosphate (IP3) synthesis, a Li+ sensitive
intracellular
signal. However, it was unclear how PO could influence either Li+
sensitivity
or risk of bipolar disorder. Here we show that in both Dictyostelium and
cultured human cells PO acts via Multiple Inositol Polyphosphate
Phosphatase (Mipp1) to control gene expression. This reveals a novel,
gene regulatory network that modulates inositol metabolism and Li+
sensitivity. Among its targets is the inositol monophosphatase gene
IMPA2,
which has also been associated with risk of bipolar disorder in some
family
studies, and our observations offer a cellular signalling pathway in
which
PO activity and IMPA2 gene expression converge.
Submitted by Adrian Harwood [[log in to unmask]]
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[End dictyNews, volume 34, number 11]
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