A catalytic polymerization model for actin-based motility

Actin-based motility is a virulence mechanism exploited by invasive bacteria and viruses to promote cell-to-cell spreading. Pathogens achieve motility by co-opting components of the cytoskeleton and mimicking the cellular processes in which they are involved. The bacteria Listeria monocytogenes, Rickettsia conorii, Shigella flexneri, and the virion Vaccinia stimulate actin polymerization through mimicking a variety of signals: N-WASP activation of Arp2/3 (Listeria), Cdc42 activation of N-WASP (Shigella), tyrosine-kinase signaling (Vaccinia) and VASP mediated filopodial extension (Rickettsia). The protein components involved in Listeria motility have been isolated and used to study the in vitro details of the motile process. High-resolution biophysical studies of Listeria have revealed that the fast-growing ends of actin filaments remain attached to bacteria during propulsion, calling into question Brownian ratchet models for actin-based movement. Listeria move in discrete steps of 5.4 nm (the actin filament subunit repeat distance) while working against forces as high as 200 pN. At higher velocities, the bacterium takes larger steps (6.0 nm), challenging elastic molecular ratchet models.; Actin is a highly conserved protein, with little evolutionary divergence across all eukaryotic species. Actin is the chief substituent of the cell's cytoskeleton and exists in both monomeric and polymeric forms. The transition from monomer (g-actin) to helical polymer (f-actin) involves the hydrolysis of the bound nucleotide, adenosine 5' -triphosphate (ATP), to the adenosine 5'-diphosphate (ADP) and inorganic phosphate (Pi). In crystal structures of the cytoskeletal isoform of actin, beta-actin, bound to ATP, actin monomers were observed as planar "ribbons" which could be converted into the electron microscopically observed helical conformation via a collapse of 0.83 nm and a rotation of 13°. It has been hypothesized that this conformational change would be preceded by release of the inorganic phosphate, and the energy released could be coupled to the development of force and movement in biological systems.; Analysis of the available biochemical and structural data on pathogens which utilize actin-based motility identified functionally homologous proteins involved in propulsion. A generalized model representing these pathogens was formulated and used to develop a chemo-mechanical mechanism, based on nucleotide-coupled conformational changes in actin, for pathogenic motility. To simulate this mechanism, a cellular automaton was implemented in which the decision-making step was replaced with a Heisenberg spin-lattice energy function in order to better approximate the protein interactions. Analysis of the mechanism and the simulation results revealed that this model reproduces the observed velocities of the various pathogens, and step size and forces measured for Listeria monocytogenes.