Adhesion energy can regulate vesicle fusion and stabilize partially fused states

Abstract

Release of neurotransmitters from nerve terminals occurs by fusion of synaptic vesicles with the plasma membrane, and this process is highly regulated. Although major molecular components that control docking and fusion of vesicles to the synaptic membrane have been identified, the detailed mechanics of this process is not yet understood. We have developed a mathematical model that predicts how adhesion forces imposed by docking and fusion molecular machinery would affect the fusion process. We have computed the membrane stress that is produced by adhesion-driven vesicle bending and find that it is compressive. Further, our computations of the membrane curvature predict that strong adhesion can create a metastable state with a partially opened pore that would correspond to the 'kiss and run' release mode. Our model predicts that the larger the vesicle size, the more likely the metastable state with a transiently opened pore. These results contribute to understanding the mechanics of the fusion process, including possible clamping of the fusion by increasing molecular adhesion, and a balance between 'kiss and run' and full collapse fusion modes.

Coarse-Grained Model of SNARE-Mediated Docking

“…During this process, the vesicle and plasma membrane both deform considerably and the task of the continuum model is to obtain a consistent solution of the deformed shape subject to these forces. The continuum calculations are based on the formulation of Jenkins et al (26) and its extension to SNARE-mediated fusion by Long et al (27). Our axisymmetric continuum model extends these formulations to include concentrated forces due to the SNARE molecules and the electrostatic forces due to the charges on the membranes or hydration repulsion.…”

“…The SNARE CG model is calibrated to match the peak unzipping force determined by Gao et al (8), and is used to calculate a force displacement curve for the unzipping process, along with snapshots of corresponding structures that provide information about the unzipping pathway. The continuum model for bilayer deformation is based on lipid membrane theory developed in Jenkins et al (26) and is an extension of work done in Long et al (27). It computes the force required to counter the vesicle-membrane repulsion, bringing the vesicle to a given distance from the membrane while taking full account of the vesicle and membrane deformation.…”

SNARE ‐mediated membrane fusion arrests at pore expansion to regulate the volume of an organelle

“…The resulting, here-predicted minimal pore size (~1.5 nm) should in principle allow free passage of small molecules, such as the fluorescent lumenal markers that we had used. Since those did, however, not pass the pores between vacuoles, additional factors should constrain pore size in vivo, such as (electrostatic) attractions within the pore interior (Han & Jackson, 2005) or adhesive interactions within the docked contact zone (Hickey & Wickner, 2010;Hernandez et al, 2012;Long et al, 2012;Bharat et al, 2014;Hishida et al, 2017). The latter can originate from tethering factors and electrostatic interactions between the apposed membrane leaflets (Hernandez et al, 2012;Bharat et al, 2014;Hishida et al, 2017).…”

“…Trans-SNARE complexes transmit force to the membranes, which drives fusion reactions through these steps (Gao et al, 2012;Hernandez et al, 2012Hernandez et al, , 2014Shi et al, 2012). Theory indicates that the expansion of an existing fusion pore faces a major energy barrier, which may be overcome through membrane tension (Chizmadzhev et al, 2000;Kozlov et al, 2010;Long et al, 2012;Kozlov & Chernomordik, 2015;Ryham et al, 2016). This suggests that expansion of fusion pores might be rate-limiting, reversible, and give rise to a potentially longlived intermediate.…”

A continuum model of docking of synaptic vesicle to plasma membrane

“…In the following, we use the formulation of Jenkins [17,36] and Long et al [37] to derive the governing equations for the deformation of the spherical vesicle and the flat plasma membrane. The undeformed configuration of the vesicle is a sphere of radius R with arc length in a cross section denoted by S, whereas the plasma membrane occupies the interior of a circle of radius L ) R. We introduce the notation f to denote the angle made by the tangent to a point on the cross section of the deformed membrane in the (r, z) plane with the z-axis (figure 2a).…”