How pruning the cytoskeleton moves the cell
Scientists have unraveled the enigmatic mechanism behind actin branching


Date:
September 20, 2021
Source:
Max Planck Institute of Molecular Physiology
Summary:
Cells are characterized to be stable yet highly flexible. They
constantly modify their shape and even move through tissue. These
vital properties are based on a dynamically organized network of
branched actin filaments, which generates pushing forces to move
the cell membrane. An interdisciplinary team has now revealed a
previously unknown mechanism, explaining how stopping the growth
of older actin filaments within the network promotes the formation
of new ones, thereby maintaining the structure and function of
the cytoskeleton, much like proper pruning of hedges in the garden.



FULL STORY ========================================================================== Cells are characterized to be stable yet highly flexible. They
constantly modify their shape and even move through tissue. These vital properties are based on a dynamically organized network of branched actin filaments, which generates pushing forces to move the cell membrane. An interdisciplinary team lead by Peter Bieling and Stefan Raunser from the
Max Planck Institute of Molecular Physiology (MPI) in Dortmund has now
jointly revealed a previously unknown mechanism, explaining how stopping
the growth of older actin filaments within the network promotes the
formation of new ones, thereby maintaining the structure and function
of the cytoskeleton, much like proper pruning of hedges in the garden.


========================================================================== Cells grow, divide, change their shape and move. They provide structure
for the body and tissues, enter wounds to close them or chase down
bacteria in our blood. The mobility of cells is a prerequisite for
a variety of essential biological functions and is ensured by the
cytoskeleton. This dynamic protein network assembles on the inside of
the cell membrane and is responsible for the cell's shape, its mechanical stability and it's ability to move.

How tiny molecules assemble into large powerful structures One key
component of the cytoskeleton is actin, which can self-assemble into
filaments. But where does the pushing force of the cytoskeleton actually originate from? The origin lies in a nucleation process that occurs
just beneath the cell membrane. Nucleation of new actin filaments is
initiated by a protein complex called Arp2/3, which is activated by membrane-bound nucleation promoting factors (NPF). The Apr2/3 forms the
initial seed of a new filament and connects this seed to the side of
older filaments. After the initial formation of this actin seed, further
actin monomers attach and construct a filament, which grows against the membrane. This growth process generates the pushing force. The resulting structure of the actin network looks like a tree or a hedge, with many connected branches of actin filaments.

Trimming the actin hedge promotes the growth of new filaments To ensure
optimal power transmission to the plasma membrane, the branched actin
network requires continuous maintenance. A key player in this process
is the capping protein. Its main task is to stop the elongation of
filaments before they become too long and to prevent the non-productive elongation of filaments that grow away from the cell membrane. Capping
actin filaments thus has a similar effect to trimming a hedge: it keeps
the (actin) hedge neat and tidy, much like proper pruning However,
it also stimulates the budding production (actin branching) near the
plant's edges (membrane) through the Arp2/3 complex.

The precise mechanism involved in how the capping protein controls the
speed by which Arp2/3 forms new filaments was not previously understood.

How a molecular tentacle regulates branching An interdisciplinary team of structural biologists and biochemists from the MPI in Dortmund, together
with cell biologists from Braunschweig University, has now uncovered the
so far enigmatic mechanism behind the opposing function of the capping
protein in the branched network assembly. A high-resolution structure
of the capping protein bound to an actin filament-end produced by co-
first author Felipe Merino using electron cryo-microscopy revealed that
the capping protein does much more than previously assumed. It not only
stops filament growth, but also blocks the end from interacting with
other proteins.

Most importantly, it blocks the binding of nucleation promoting factors
(the Arp2/3 activators) via a tiny "tentacle" extension. Johanna Funk,
co-first author of the study, was able to show, that removing this
tentacle did not prevent the capping protein from stopping filament
growth, but drastically inhibited the network assembly and the efficiency
of lamellipodial protrusion required for cell movement when working
together with all other proteins required to build branched networks.

"Studying the role of the capping protein from many different angles
has uncovered details about how the core proteins that build branched
actin networks do not act as separate players as previously thought, but
really as a functional unit. We hope, that our findings will contribute
to a better understanding of cell movement of both healthy as well as
diseased cells in the future," says Peter Bieling.

========================================================================== Story Source: Materials provided by Max_Planck_Institute_of_Molecular_Physiology. Note: Content may be edited
for style and length.


========================================================================== Journal Reference:
1. Jun Yu, Pierre Raia, Chloe M. Ghent, Tobias Raisch, Yashar Sadian,
Simone
Cavadini, Pramod M. Sabale, David Barford, Stefan Raunser, David O.

Morgan, Andreas Boland. Structural basis of human separase
regulation by securin and CDK1-cyclin B1. Nature, 2021; 596 (7870):
138 DOI: 10.1038/ s41586-021-03764-0 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/09/210920121753.htm

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