Mechanism of negative membrane curvature generation by I-BAR domains

Abstract

The membrane sculpting ability of BAR domains has been attributed to the intrinsic curvature of their banana-shaped dimeric structure. However, there is often a mismatch between this intrinsic curvature and the diameter of the membrane tubules generated. For example, I-BAR domains are almost flat but generate much higher membrane curvature. Furthermore, F-BAR and I-BAR domains are quite similar, but the former generates positive curvature and the latter negative curvature. Here, we use implicit-solvent computer modeling to show that the membrane bending of the IRSP53 I-BAR domain is dictated by its oligomeric structure, whose curvature is completely unrelated to the intrinsic curvature of the dimer. We find that I-BAR dimers undergo lateral and end-to-end interactions to form higher oligomers. The lateral interactions, which can occur with varying register, are stronger and give a curved shape that has the membrane binding interface on its convex surface. Two other I-BARs (MIM and I-BARa) gave similar results, whereas a flat F-BAR sheet curved to make its membrane binding interface concave, consistent with positive membrane curvature generation. Individual dimers orient parallel to the tube axis when the tube radius is small, whereas perpendicular orientation is preferred for larger diameter tubes. This orientational preference exists even in the higher oligomeric form. Helical spirals on tube interiors are stable at a density comparable to experimental measurements. The sorting ratio computed from our membrane binding energies is also consistent with experimental measurements.

Membrane curvature catalyzes actin nucleation through nano-scale condensation of N-WASP-FBP17

“…In vitro studies have shown the SH3 domain of these proteins can directly activate N-WASP-mediated actin polymerization on liposomes with a specific diameter 21,26 . The other BAR proteins, like I-BAR (IRSp53), recruit actin regulatory proteins like VASP, mDia2 and WAVE2 through SH3 domain interaction 27,[60][61][62][63][64][65][66][67] . Our research now clarifies how the SH3 domain contributes to nanoscale N-WASP clustering upon precise curvature sensing by BAR, promoting localized Arp2/3 activation and robust actin nucleation.…”