A common mechanism for protein cluster formation

Abstract

Polarized states on the membranes are characterized by focal accumulation of proteins and lipids at local concentrations far exceeding their levels typically found outside of these dense clusters. Principles of thermodynamics argue that formation and maintenance of such structures require continuous expenditure of cellular energy to combat the effect of molecular diffusion that relentlessly dissipates the clusters in favor of the spatially homogeneous state. Small GTPases are known to play a crucial role in the formation of several such polarized states. Their ability to consume stored energy and convert it into a potentially useful work by cyclically hydrolyzing GTP and coupling to various effectors in a nucleotide-dependent way, makes them eligible candidates to fulfill the requirements for the molecules involved in the mechanisms responsible for the maintenance of polarized states. Consistently, continuous nucleotide cycling of small GTPases has been found required for the emergence of structures in several well characterized cases. Despite this general awareness, the detailed molecular mechanisms remain largely unknown. In a recent study, not directly involving small GTPases, we proposed a mechanism explaining the emergence and maintenance of the stable cell-polarity landmark that manifests itself as a protein cluster positioned on the plasma membrane at the growing ends of fission yeast cells. Unexpectedly, this study has suggested a number of striking parallels with the mechanisms based on the activity of small GTPases. These findings highlight common design principles of cellular pattern-forming mechanisms that have been mixed and matched in various combinations in the course of evolution to achieve the same desired outcome-tightly controlled in space and time formation of dense protein clusters.

Figure 1

A class of membrane structures that are maintained in steady state by continuous convective cycling of their components. (A) Cdc42 is rapidly activated on the membrane in the center of the presumptive bud site due to the high local concentration of its GEF Cdc24. While diffusing along the membrane toward the periphery, Cdc42 is progressively deactivated and leaves the membrane. Nucleotide cycling of Cdc42 provides energy to drive continuous convective flux of Cdc42, its effectors and Cdc24. Vesicular traffic is not shown for simplicity. (B) Tea1 is delivered by microtubules onto the membrane at the cell tips, where, with the help of Mod5, it is partially incorporated into the Tea1 polymer. Mod5 that resides on the membrane and thus does not participate in the membrane-cytoplasmic cycle is not shown for simplicity. Drifting away polymer is depolymerized and Tea1 is recycled back to the cytoplasm to be captured by growing microtubules and re-enter the cycle. The convective flux of Tea1 is driven by the energy consumed by Tea2 kinesin motors (thin straight arrows) and by the polymerizing tubulin (thick short arrows). Bell-shaped curves represent symbolically the membrane concentration profiles of the activated Cdc42 (A) and Tea1 (B), respectively.