A Model for Myomerger Function in Myoblast Fusion

Abstract

Myomerger, an integral membrane protein, has been recently established to play a crucial role in myoblast fusion by driving the transition from the hemifusion to the full fusion stage of the reaction. To accomplish this task, the ectodomains of myomerger molecules located at the proximal (outer) leaflets of the fusing plasma membranes must be able to mediate formation of a fusion pore in the hemifusion diaphragm (HD), which consist of the distal (inner) membrane leaflets. We now report that, similarly to myomerger, the phospholipid lysophosphatidylcholine (LPC) promotes hemifusion-to-fusion transition, if added to the proximal leaflets of the hemifused membranes. An apparent similarity between LPC and myomerger consists in their ability to generate a positive spontaneous curvature of lipid monolayers. This effect of LPC is known to be driven by its effective molecular shape, while myomerger could act through insertion of its N-terminal amphipathic domain into the membrane matrix. Here we propose a mechanism of indirect promotion of the fusion pore formation. The essence of the mechanism is a geometrical and mechanical coupling of the proximal and distal leaflets of the fusing membranes mediated by the HD rim. The elastic stresses generated by LPC and/or myomerger in the distal membrane leaflets are transmitted through the HD rim into the leaflets of the hemifusion diaphragm, which facilitates the fusion pore generation and growth. To substantiate the mechanism, using the theory of the membrane bending, splay and tilt elasticity, we computed the elastic stresses propagating into the HD as functions of LPC concentration in the proximal membrane leaflets, determined the effective values of HD line tension and calculated the kinetic barriers of the fusion pore formation. We predicted, quantitatively, the degree of acceleration of the fusion pore formation by relevant LPC amounts in the membrane.