A kinetic basis for curvature sensing by septins

Shi, W.; Cannon, K. S.; Curtis, B. N.; Edelmaier, C.; Gladfelter, A. S.; Nazockdast, E.

doi:10.1101/2022.05.16.492121

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bioRxiv · 10.1101/2022.05.16.492121

A kinetic basis for curvature sensing by septins

Shi, W.·Cannon, K. S.·Curtis, B. N.·Edelmaier, C.·Gladfelter, A. S.·Nazockdast, E.

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Abstract

The ability of cells to sense and communicate their shape is central to many of their functions. Much is known about how cells generate complex shapes, yet how they sense and respond to geometric cues remains poorly understood. Septins are GTP-binding proteins that localize to sites of micron-scale membrane curvature. Assembly of septins is a multi-step and multi-scale process but it is unknown how these discrete steps lead to curvature sensing. Here we experimentally examine the time-dependent binding of septins at different curvatures and septin bulk concentrations. These experiments unexpectedly indicated that the curvature preference of septins is not absolute but rather is sensitive to the combinations of membrane curvatures present in a reaction, suggesting there is competition between different curvatures for septin binding. To understand the basis of this result, we developed a kinetic model that connects septins self-assembly and curvature sensing properties. Our experimental and modeling results are consistent with curvature-sensitive assembly being driven by cooperative associations of septin oligomers in solution with the bound septins. When combined, the work indicates septin curvature sensing is kinetically determined, sensitive to bulk concentration, and the available membrane curvatures. While much geometry-sensitive assembly in biology is thought to be guided by intrinsic material properties of molecules, this is an important example of how kinetics can drive mesoscale curvature-sensitive assembly of polymers. Significance StatementCells use their membrane curvature to coordinate the activation and spatiotemporal compartmentalization of molecules during key cellular processes. Recent works have identified different proteins that can sense or induce membrane curvature from nano- to micron-scale. Septins are nanoscopic cytoskeletal proteins that preferentially bind to membranes with a narrow range of micron-scale curvatures. Yet the sensing mechanism remains ambiguous. Using a combination of microscopy and kinetic modeling, we show that, unlike most proteins that sense curvature in a single protein scale, curvature sensing in septins is determined kinetically through their multi-step hierarchical assembly on the membrane. This introduces a novel kinetic basis of fidelity, where the same protein can be deployed for differential binding sensitivities in different cellular contexts.

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Shi, W., Cannon, K. S., Curtis, B. N., Edelmaier, C., Gladfelter, A. S., Nazockdast, E.. 2022-05-17. A kinetic basis for curvature sensing by septins. https://doi.org/10.1101/2022.05.16.492121

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