Further, previous work found that disordered domains, which occupy large footprints on the membrane surface in comparison to well-folded proteins of equal molecular weight ( Hofmann et al., 2012), enhanced the efficiency of membrane bending and fission ( Busch et al., 2015 Snead et al., 2017). Recent work from our laboratory ( Stachowiak et al., 2010, 2012) and others ( Vennema et al., 1996 Bhagatji et al., 2009 Copic et al., 2012 Jiang et al., 2013 Wu et al., 2014) has revealed that molecular crowding among proteins attached to membrane surfaces at high density generates steric pressure, which provides a potent force for membrane shaping. How might these disordered domains influence the membrane remodeling behavior of BAR domains? However, BAR domains do not typically exist in isolation in the cell, but rather as part of large, multi-domain proteins that also frequently contain long, intrinsically disordered protein (IDP) domains of several hundred amino acids ( Miele et al., 2004 Lee et al., 2007 Henne et al., 2010 Roberts-Galbraith and Gould, 2010 Wuertenberger and Groemping, 2015). These results have provided critical insight into the detailed geometry of BAR domain arrangement at membrane surfaces, helping to elucidate their mechanisms of membrane curvature sensing and induction. Examples include the N-terminal amphipathic helix BAR (N-BAR) domain of amphiphysin ( Peter et al., 2004), the FCH BAR (F-BAR) domain of FCHo1/2 ( Henne et al., 2007, 2010), the F-BAR domain of the neuronal migration protein srGAP2 ( Guerrier et al., 2009), the F-BAR domains of the cytokinesis proteins Imp2 ( McDonald et al., 2016) and Cdc15 ( McDonald et al., 2015), and the inverted BAR (I-BAR) domains of MIM and ABBA ( Mattila et al., 2007 Saarikangas et al., 2009), among others. Importantly, many in vitro studies on the membrane shaping behavior of BAR domains have examined the BAR domain in isolation, with significant portions of the protein removed. ![]() In living cells, BAR scaffolds are thought to assemble into more limited scaffolds that shape membranes in concert with other proteins, including the dynamin fission machine and the actin cytoskeleton ( Itoh et al., 2005 Ferguson et al., 2009 Renard et al., 2015). Notably, this perspective comes primarily from studies performed in vitro. This rigid scaffold has been hypothesized to stabilize membrane tubules, preventing their division into separate membrane compartments through the process of membrane fission ( Boucrot et al., 2012). For example, the crescent-shaped, dimeric bin-amphiphysin-rvs (BAR) domains ( Frost et al., 2009 Mim and Unger, 2012 Simunovic et al., 2015) polymerize into cylindrical scaffolds on membrane surfaces, forcing the underlying membrane to adopt the tubular geometry of the scaffold ( Frost et al., 2008 Mim et al., 2012 Adam et al., 2015). Since membranes resist deformation ( Helfrich, 1973), cells employ specialized protein machines to drive membrane remodeling ( Zimmerberg and Kozlov, 2006). These data suggest that the ability to concentrate disordered domains is a key driver of membrane remodeling and fission by BAR domain–containing proteins.Ĭellular membranes must undergo dynamic remodeling to facilitate essential cellular processes, including formation of trafficking vesicles ( Conner and Schmid, 2003), viral egress ( Hurley et al., 2010), and cytokinesis ( Mierzwa and Gerlich, 2014). More broadly, we observe this behavior with BAR domains that have a range of curvatures. ![]() Specifically, when BAR scaffolds assemble at membrane surfaces, their bulky disordered domains become crowded, generating steric pressure that destabilizes lipid tubules. Using in vitro and live cell assays, here we show that full-length BAR domain–containing proteins, rather than stabilizing membrane tubules, are instead surprisingly potent drivers of membrane fission. But in nature, proteins that contain BAR domains often also contain large intrinsically disordered regions. Based on studies of isolated BAR domains in vitro, the current paradigm is that BAR domain–containing proteins polymerize into cylindrical scaffolds that stabilize lipid tubules. The crescent-shaped bin-amphiphysin-rvs (BAR) domains remodel membranes in multiple cellular pathways. Cellular membranes are continuously remodeled.
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