Biology subjects

Edelmaier, C.

Publications and source records attributed to Edelmaier, C..

4 recordsLinked to original sources

bioRxiv2025

Study of Protein-Protein Interactions in Septin Assembly: Multiple amphipathic helix domains cooperate in binding to the lipid membrane

Septins are a conserved family of cytoskeletal proteins known for sensing micron-scale membrane curvature via amphipathic helix (AH) domains. While cooperative interactions in septin assembly have been suggested, the molecular mechanisms governing membrane binding and assembly remain unclear. Building on prior findings, we use all-atom molecular dynamics simulations to examine how single and paired extended AH domains, derived from Cdc12, interact with lipid bilayers. A single membrane-bound AH adopts a curved conformation. In solution, a second AH peptide preferentially interacts with the bound peptide through conserved salt bridges, favoring an antiparallel arrangement. Simulations of covalently linked AH tandems confirm this configuration. Dual membrane-bound peptides induce lipid packing defects, reduce tail order, and exhibit slight membrane displacement, suggesting curved membranes may better accommodate multiple AH domains. Our findings advance the mechanistic understanding of septin-membrane interactions and highlight the role of cooperative AH domain binding in stabilizing higher-order structures.

biophysics↗

bioRxiv2025

Lipid packing and local geometry influence septin curvature sensing

Septins assemble into scaffolds that direct cell growth and morphology that are often localized to the plasma membrane. While septins preferentially bind convex membranes via amphipathic helices, their assembly on varied geometries in cells suggests additional localization cues. We tested the hypothesis that lipid composition directs septin assembly through lipid packing properties. Lipid mixtures varying in lipid packing were designed by molecular dynamics simulations and incorporated onto supported lipid bilayers to measure septin adsorption in vitro. Septins strongly favor loosely-packed, disordered lipid bilayers but additional geometry cues act in conjunction with this membrane property. Introducing tighter lipid packing in cells disrupted septin structures in a curvature dependent manner, specifically limiting septin assembly and retention along flat regions of the plasma membrane. This work demonstrates that packing defects and geometry jointly regulate septin localization and highlights how multiple membrane properties are integrated to control organization of the septin cytoskeleton. SummaryLocalization of the septin cytoskeleton is controlled by regulatory factors, membrane curvature, and charge. In this study, changes to lipid composition that modulate lipid packing defects are found to impact septin assemblies in vitro and in cells.

biochemistry↗

bioRxiv2022

A kinetic basis for curvature sensing by septins

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.

biophysics↗

bioRxiv2018

Theory of cytoskeletal reorganization during crosslinker-mediated mitotic spindle assembly

Cells grow, move, and respond to outside stimuli by large-scale cytoskeletal reorganization. A prototypical example of cytoskeletal remodeling is mitotic spindle assembly, during which micro-tubules nucleate, undergo dynamic instability, bundle, and organize into a bipolar spindle. Key mechanisms of this process include regulated filament polymerization, crosslinking, and motor-protein activity. Remarkably, using passive crosslinkers, fission yeast can assemble a bipolar spindle in the absence of motor proteins. We develop a torque-balance model that describes this reorganization due to dynamic microtubule bundles, spindle-pole bodies, the nuclear envelope, and passive crosslinkers to predict spindle-assembly dynamics. We compare these results to those obtained with kinetic Monte Carlo-Brownian dynamics simulations, which include crosslinker-binding kinetics and other stochastic effects. Our results show that rapid crosslinker reorganization to microtubule overlaps facilitates crosslinker-driven spindle assembly, a testable prediction for future experiments. Combining these two modeling techniques, we illustrate a general method for studying cytoskeletal network reorganization.

cell biology↗