Directed and persistent movement arises from mechanochemistry of the ParA/ParB system

Abstract

The segregation of DNA before cell division is essential for faithful genetic inheritance. In many bacteria, segregation of low-copy number plasmids involves an active partition system composed of a nonspecific DNA-binding ATPase, ParA, and its stimulator protein ParB. The ParA/ParB system drives directed and persistent movement of DNA cargo both in vivo and in vitro. Filament-based models akin to actin/microtubule-driven motility were proposed for plasmid segregation mediated by ParA. Recent experiments challenge this view and suggest that ParA/ParB system motility is driven by a diffusion ratchet mechanism in which ParB-coated plasmid both creates and follows a ParA gradient on the nucleoid surface. However, the detailed mechanism of ParA/ParB-mediated directed and persistent movement remains unknown. Here, we develop a theoretical model describing ParA/ParB-mediated motility. We show that the ParA/ParB system can work as a Brownian ratchet, which effectively couples the ATPase-dependent cycling of ParA-nucleoid affinity to the motion of the ParB-bound cargo. Paradoxically, this resulting processive motion relies on quenching diffusive plasmid motion through a large number of transient ParA/ParB-mediated tethers to the nucleoid surface. Our work thus sheds light on an emergent phenomenon in which nonmotor proteins work collectively via mechanochemical coupling to propel cargos-an ingenious solution shaped by evolution to cope with the lack of processive motor proteins in bacteria.ParA ATPase | Brownian ratchet | theoretical model | motility

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“…The basis for communication remains to be established. In general, patterns can be achieved in either of two ways (or by a combination of both) (for examples in a bacterial system, see 94–96). At one extreme, the chromosomes per se are an essentially passive substrate upon which biochemical events occur in a "reaction-diffusion" process.…”

Brownian ratchet mechanisms of ParA-mediated partitioning

“…The conceptual underpinning of different ParA-mediated Brownian ratchet models, including the “DNA-relay model” (6), “hitch-hiking model” (5), and our mechanochemical coupling-mediated Brownian ratchet model (3, 4, 14–16), is essentially the same. All three can be considered as burnt-bridge Brownian ratchets, as originally proposed in (3, 4, 15).…”

“…As proposed by our original ParA-mediated Brownian ratchet model (3, 4, 15), this free energy gradient results in a so-called “chemophoresis” force (energy descent/distance) (19) that could direct the cargo movement (3, 4, 15). From the standpoint of chemical bonds, this asymmetric distribution of the ParA–ParB bonds bridging the cargo with the substrate provides a net force that pulls the cargo forward (6, 14, 16). Regardless of the mode of driving force, all the ParA-mediated Brownian ratchet models agree that the asymmetric ParA distribution is necessary for directed and persistent cargo movement (3–6, 14–16), as originally proposed (3, 4, 15).…”

The Slow Mobility of the ParA Partitioning Protein Underlies Its Steady-State Patterning in Caulobacter

“…For plasmid-encoded ParABS systems, it has been proposed that localized ParB stimulation of ParA ATPase activity, coupled with 1) uniform redistribution of ParA on the nucleoid due to a time delay in ParA rebinding to the DNA and 2) diffusion of the ParB-coated cargo generates a propagating ParA wave (1,8). This idea was suggested from in vitro experiments with ParBcoated beads and plasmid clusters (9)(10)(11)(12).…”