BAR scaffolds drive membrane fission by crowding disordered domains

Wilton T. Snead; Wade F. Zeno; Grace Kago; Ryan W. Perkins; J Blair Richter; Chi Zhao; Eileen M. Lafer; Jeanne C. Stachowiak

Importantly, most studies on the membrane shaping behavior of BAR domains have examined the BAR domain in isolation, with significant portions of the protein removed. 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., 2010; Henne et al., 2007) , 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. 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. However, BAR domains do not typically exist in isolation in the cell, but rather as part of large, multi-domain proteins which also frequently contain long, intrinsically-disordered protein (IDP) domains of several hundred amino acids (Henne et al., 2010; Lee et al., 2007; Miele et al., 2004; Wuertenberger and Groemping, 2015) . How might these disordered domains influence the membrane remodeling behavior of BAR domains? cells -what brings bulky domains together to generate steric pressure? In particular, what keeps crowded proteins from simply diffusing away from one another, dissipating steric pressure and inhibiting membrane shaping? Proteins such as amphiphysin (Miele et al., 2004; Peter et al., 2004) and FCHo1/2 (Henne et al., 2010; Henne et al., 2007) , which contain both scaffold-forming BAR domains and bulky disordered domains, present a possible solution to this problem. Specifically, the ability of BAR domains to form scaffolds has the potential to locally concentrate disordered domains such that steric pressure is amplified rather than dissipated.