Computer Simulations of Mechano-Chemical Networks Choreographing Actin Dynamics in Cell Motility - Computational Modeling of Biological Systems - page 249

4.2.2 The Antagonism Between Capping and Anti-capping Proteins

Affects Actin Network Dynamics

Capping proteins and anti-capping proteins such as formin and Ena/VASP are
key regulators of actin network dynamics [ 87 , 88 ]. Capping proteins block the
polymerization of actin filaments, thus, one might expect them to inhibit motility.
Motility inhibition by capping proteins occurs just as expected at sufficiently high
concentrations of capping proteins. However, at modest concentrations, capping
proteins can increase the speed of actin-based motility [ 35 , 78 , 80 , 89 - 91 ]. This
interesting phenomenon was explained by two fundamentally different ideas: the
actin funneling hypothesis [ 89 ] proposes that capping proteins increase the rate
of individual growing barbed ends by reducing their number, while the monomer
gating model [ 91 ] suggests that motility enhancement is due to more frequent
filament nucleation. Motivated by these studies, stochastic simulations [ 35 , 80 ]
based on microscopic chemical physics have been carried out to investigate the
mechanism of capping proteins promoting motility. The advantage of computer
simulation is that it offers great details on various microscopic quantities involved
in motility process for analysis: it was found that with capping proteins, on
average, there are more actin monomers available for polymerization, leading to
the faster rate of polymerization at low capping protein concentrations, which
is in agreement with the actin funneling hypothesis; although capping proteins
indeed promote nucleation of filaments, also the consequence of increased local
actin concentration, many filaments become capped and lag behind the leading
edge of the membrane, resulting in a diminution of the filament density along the
leading edge of the membrane. This, in turn, leads to higher load on polymerizing
filaments, unfavorable to polymerization process, especially at high capping protein
concentrations.
On the other hand, anti-capping proteins compete with capping proteins for
barbed ends binding, thereby affecting actin dynamics by keeping filament density
at leading edge from being diminished by capping proteins. This, in turn, affects fil-
ament polymerization since the average local actin concentration for polymerization
and the average load on polymerizing filaments are highly correlated to the density
of leading edge filaments. It should be pointed out that anti-capping proteins such as
formins can increase the rate of polymerization dramatically. This polymerization
rate enhancement function by anti-capping proteins makes the dynamic behavior
of the motility system even more diverse [ 80 ]. In particular, it turns out that the
coupling of the capping/anti-capping regulation with Arp2/3 nucleation activity
allows the cell to robustly achieve maximal protrusion speed under broad set of
conditions [ 80 ].
In summary, protrusion dynamics in a motility system containing capping
proteins may display both the enhanced and inhibited behaviors, which can be
significantly affected by the presence of anti-capping proteins. Detailed analysis
of microscopic quantities obtained from stochastic simulations offers great insight
on the protrusion dynamics of lamellipodial-like branched network, allowing to
discriminate among competing qualitative hypotheses. Furthermore, it is known