Geometric Catalysis of Membrane Fission Driven by Flexible Dynamin Rings

Abstract

Biological membrane fission is conducted by protein-driven stress. To create such membrane stress the GTPase dynamin-1, protein orchestrating membrane fission in endocytosis, assembles into helical scaffolds that constrict the necks of endocytic vesicles. We found that under constant GTP turnover two-rung dynamin scaffold is sufficient to produce fission of lipid nanotubes. Analyzing membrane fission by short dynamin scaffolds, we reveal a catalytic cycle which translates constriction stresses into fission. Upon constriction, coordinated membrane wedging by the scaffold facilitates reversible merger of the inner leaflet of the nanotube, the hemifission. Modeling of this reversible step identifies a low-energy path based on geometric coupling of the scaffold and the membrane. The final translation of the metastable hemifission into complete fission is stochastically linked to disassembly of the scaffold. This catalytic conversion of localized stresses into membrane remodeling suggests a novel paradigm for fission and fusion of cellular membranes.

Dual Role of BAR Domain-containing Proteins in Regulating Vesicle Release Catalyzed by the GTPase, Dynamin-2

“…2C). Previous studies have shown that dynamin-catalyzed membrane fission is a stochastic process involving many, apparently futile cycles of assembly/ disassembly driven by GTP hydrolysis (7,40,41). While we cannot directly measure the relationship between GTP hydrolysis and individual membrane fission events, these data suggest that the presence of the N-BAR domain increases the efficiency of coupling between dynamin GTPase activity and membrane fission.…”

“…Shorter scaffolds would lead to overall decreased rates of GTP hydrolysis, which depends on inter-rung interactions (56) and may be critical in facilitating fission activity, because the formation of long scaffolds on membrane tubules/CCP necks will inhibit fission (7,32,41). Indeed, recent biophysical measurements and modeling studies of dynamin-catalyzed fission on small lipid nanotubes showed that the optimal fission apparatus consists of a two-rung dynamin collar (40). The authors suggested that one role for GTP hydrolysis and accompanying cycles of assembly/ disassembly was to restrict and optimize the size of these short functional units.…”

Dynamin-related Protein 1 (Drp1) Promotes Structural Intermediates of Membrane Division

“…Moreover, these GTP-induced Drp1 clusters were also present along the tubes with a similar distribution pattern as dynamin (48,54), suggesting that those sites could represent potential nucleation points for mitochondrial fission. Along these lines, previous work reported that long dynamin scaffolds did not produce membrane scission, whereas GTPase-dependent cycles of assembly and stochastic disassembly of short dynamin scaffolds led to fission (66,75).…”

Building a fission machine – structural insights into dynamin assembly and activation

“…Recent studies argue that fission might instead be driven by partial disassembly of the dynamin polymer (Pucadyil and Schmid, 2008;Bashkirov et al, 2008), curvature-dependent changes in elastic energy at the edge of the dynamin polymer (Morlot et al, 2012) or PH domain tilting within short metastable dynamin collars (Shnyrova et al, 2013). These models disagree on the role of stimulated GTP hydrolysis, despite the fact that this activity is absolutely required for fission in vitro (Liu et al, 2013) and efficient endocytosis in vivo (Chappie et al, 2010).…”

“…Structural comparison shows that changes in the stalk density, presumably induced by nucleotide binding, drive the tube constriction (Chen et al, 2004). However, other data indicates that constriction alone is not sufficient to produce scission (Bashkirov et al, 2008;Shnyrova et al, 2013), suggesting that these EM models represent an intermediate along the endocytic scission pathway. Saccharomyces cerevisiae Dnm1 tubes also constrict, but exhibit a more dramatic narrowing from ,129 nm to ,67 nm that is associated with GTP hydrolysis .…”