Biology subjects

Jarin, Z.

Publications and source records attributed to Jarin, Z..

3 recordsLinked to original sources

bioRxiv2022

Activated I-BAR IRSp53 clustering controls the formation of VASP-actin-based membrane protrusions

Filopodia are actin-rich membrane protrusions essential for cell morphogenesis, motility, and cancer invasion. How cells control filopodia initiation on the plasma membrane remains elusive. We performed experiments in cellulo, in vitro and in silico to unravel the mechanism of filopodia initiation driven by the membrane curvature sensor IRSp53. We showed that full-length IRSp53 self-assembles into clusters on membranes depending on PIP2. Using well-controlled in vitro reconstitution systems, we demonstrated that IRSp53 clusters recruit the actin polymerase VASP to assemble actin filaments locally on membranes, leading to the generation of actin-filled membrane protrusions reminiscent of filopodia. By pulling membrane nanotubes from live cells, we observed that IRSp53 can only be enriched and trigger actin assembly in nanotubes at highly dynamic membrane regions. Our work supports a regulation mechanism of IRSp53 in its attributes of curvature sensation and partner recruitment to ensure a precise spatial-temporal control of filopodia initiation.

biophysics↗

bioRxiv2020

Coarse-grained Force Fields from the Perspective of Statistical Mechanics: Better Understanding the Origins of a MARTINI Hangover

The popular MARTINI coarse-grained model is used as a test case to analyze the adherence of top-down coarse-grained molecular dynamics models (i.e., models primarily parameterized to match experimental results) to the known features of statistical mechanics for the underlying all-atom representations. Specifically, the temperature dependence of various pair distribution functions, and hence their underlying potentials of mean force via the reversible work theorem, are compared between MARTINI 2.0, Dry MARTINI, and all-atom simulations mapped onto equivalent coarse-grained sites for certain lipid bilayers. It is found that the MARTINI models do not completely capture the lipid structure seen in atomistic simulations as projected onto the coarse-grained mappings, and that issues of accuracy and temperature transferability arise due to an incorrect enthalpy-entropy decomposition of these potentials of mean force. The potential of mean force for the association of two amphipathic helices in a lipid bilayer is also calculated and, especially at shorter ranges, the MARTINI and all-atom projection results differ substantially. The former is much less repulsive and hence will lead to a higher probability of MARTINI helix association in the MARTINI bilayer than occurs in the actual all-atom case. Additionally, the bilayer height fluctuation spectra are calculated for the MARTINI model and - compared to the all-atom results - it is found that the magnitude of thermally averaged amplitudes at intermediate length scales is quite different, pointing to a number of possible consequences for realistic modeling of membrane processes. Taken as a whole, the results presented here can point the way for future coarse-grained model parameterization efforts that might bring top-down coarse-grained models into better agreement with the statistical mechanics of the actual all-atom systems they aspire to represent.

biophysics↗

bioRxiv2020

Membrane-mediated Forces Can Stabilize Tubular Assemblies of I-BAR Proteins

Collective action by Inverse-BAR (I-BAR) domains drive micron-scale membrane remodeling. The macroscopic curvature sensing and generation behavior of I-BAR domains is well characterized, and computational models have suggested various mechanisms on simplified membrane systems, but there remain missing connections between the complex environment of the cell and the models proposed thus far. Here, we show a connection between the role of protein curvature and lipid clustering in the stabilization of large membrane deformations. We find lipid clustering provides a directional membrane-mediated interaction between membrane-bound I-BAR domains. Lipid clusters stabilize I-BAR domain aggregates that would not arise through membrane fluctuation-based or curvature-based interactions. Inside of membrane protrusions, lipid cluster-mediated interaction draws long side-by-side aggregates together resulting in more cylindrical protrusions as opposed to bulbous, irregularly shaped protrusions. Statement of SignificanceMembrane remodeling occurs throughout the cell and is crucial to proper cellular function. In the cellular environment, I-BAR proteins are responsible for sensing membrane curvature and initiating the formation of protrusions outward from the cell. Additionally, there is a large body of evidence that I-BAR domains are sufficient to reshape the membrane on scales much larger than any single domain. The mechanism by which I-BAR domains can remodel the membrane is uncertain. However, experiments show that membrane composition and most notably negatively-charge lipids like PIP2 play a role in the onset of tubulation. Using coarse-grained models, we show that I-BAR domains can cluster negatively charge lipids and clustered PIP2-like membrane structures facilitate a directional membrane-mediated interaction between I-BAR domains.

biophysics↗