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Aggregation and vesiculation of membrane proteins by curvature-mediated interactions


Membrane remodelling1,2,3,4,5 plays an important role in cellular tasks such as endocytosis, vesiculation and protein sorting, and in the biogenesis of organelles such as the endoplasmic reticulum or the Golgi apparatus. It is well established that the remodelling process is aided by specialized proteins that can sense4 as well as create6 membrane curvature, and trigger tubulation7,8,9 when added to synthetic liposomes. Because the energy needed for such large-scale changes in membrane geometry significantly exceeds the binding energy between individual proteins and between protein and membrane, cooperative action is essential. It has recently been suggested10,11 that curvature-mediated attractive interactions could aid cooperation and complement the effects of specific binding events on membrane remodelling. But it is difficult to experimentally isolate curvature-mediated interactions from direct attractions between proteins. Moreover, approximate theories predict repulsion between isotropically curving proteins12,13,14,15. Here we use coarse-grained membrane simulations to show that curvature-inducing model proteins adsorbed on lipid bilayer membranes can experience attractive interactions that arise purely as a result of membrane curvature. We find that once a minimal local bending is realized, the effect robustly drives protein cluster formation and subsequent transformation into vesicles with radii that correlate with the local curvature imprint. Owing to its universal nature, curvature-mediated attraction can operate even between proteins lacking any specific interactions, such as newly synthesized and still immature membrane proteins in the endoplasmic reticulum.

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Figure 1: Illustration of the individual entities used in the simulation.
Figure 2: Successive stages of a vesiculation event driven by 36 large caps on a membrane containing 46,080 lipids.
Figure 3: Attraction and cooperative budding driven by 16 capsids on a membrane containing 40,960 lipids.
Figure 4: Force versus distance for two capsids.

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We enjoyed discussions with I. R. Cooke, Ch. Peter, E.-K. Sinner, J. Guven, H.-G. Kräusslich and all members of the ESPResSo team at the MPI-P. B.J.R. acknowledges financial support from the collaborative research centre ‘From single molecules to nanoscopically structured materials’ and M.D. from an Emmy Noether fellowship, both of the Deutsche Forschungsgemeinschaft. A grant for computer time within the DEISA programme is also acknowledged.

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Correspondence to Kurt Kremer or Markus Deserno.

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Supplementary information

Supplementary Information

This file contains Supplementary Methods, Supplementary Discussion, Supplementary Figure 1 illustrating the pair-correlation function of the small and large caps, Supplementary Table 1 presenting parameters of non-bonded interactions, Supplementary Videos Legends and additional references. (PDF 400 kb)

Supplementary Video 1

This file contains Supplementary Video 1 which shows vesiculation event driven by 36 large caps (see Figure 1) on a membrane containing 46 080 lipids. First, only membrane fluctuations and clustering of the caps are visible, then after 40 000 ζ a large protein aggregate buckles the membrane and the formation of a bud is observed. The movie length is 70 700 ζ ˜ 1 ms. (MOV 12408 kb)

Supplementary Video 2

This file contains Supplementary Video 2 which shows vesiculation event driven by 36 extra large caps on a membrane containing 46 080 lipids. The caps are constructed from two layers of 106 particles which is about twice the number as the large caps in Movie S1. Aggregation of the caps into small buds can be seen. At the end of the movie, the membrane is peeled away so that the buds can be clearly seen. The movie length is 16 700 ζ ˜ 0.25 ms. (MOV 9150 kb)

Supplementary Video 3

This file contains Supplementary Video 3 which shows cooperative budding driven by 16 capsids on a membrane containing 40 960 lipids. The formation of capsid pairs is seen, followed by the budding of clusters of 3 or 4 capsids. At the end of the movie the membrane is peeled away so that the buds can be clearly seen. The movie length is 39 800 ζ ˜ 0.6 ms. (MOV 24184 kb)

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Reynwar, B., Illya, G., Harmandaris, V. et al. Aggregation and vesiculation of membrane proteins by curvature-mediated interactions. Nature 447, 461–464 (2007).

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