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Review
. 2020 Apr 21;9(4):1029.
doi: 10.3390/cells9041029.

Interdisciplinary Synergy to Reveal Mechanisms of Annexin-Mediated Plasma Membrane Shaping and Repair

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Free PMC article
Review

Interdisciplinary Synergy to Reveal Mechanisms of Annexin-Mediated Plasma Membrane Shaping and Repair

Poul Martin Bendix et al. Cells. .
Free PMC article

Abstract

The plasma membrane surrounds every single cell and essentially shapes cell life by separating the interior from the external environment. Thus, maintenance of cell membrane integrity is essential to prevent death caused by disruption of the plasma membrane. To counteract plasma membrane injuries, eukaryotic cells have developed efficient repair tools that depend on Ca2+- and phospholipid-binding annexin proteins. Upon membrane damage, annexin family members are activated by a Ca2+ influx, enabling them to quickly bind at the damaged membrane and facilitate wound healing. Our recent studies, based on interdisciplinary research synergy across molecular cell biology, experimental membrane physics, and computational simulations show that annexins have additional biophysical functions in the repair response besides enabling membrane fusion. Annexins possess different membrane-shaping properties, allowing for a tailored response that involves rapid bending, constriction, and fusion of membrane edges for resealing. Moreover, some annexins have high affinity for highly curved membranes that appear at free edges near rupture sites, a property that might accelerate their recruitment for rapid repair. Here, we discuss the mechanisms of annexin-mediated membrane shaping and curvature sensing in the light of our interdisciplinary approach to study plasma membrane repair.

Keywords: annexin; cell rupture; interdisciplinary research; membrane curvature; membrane curvature sensing; membrane damage; membrane shaping; plasma membrane repair.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Binding of annexins (green) to a planar membrane patch with free edges and adhesion energy wad inducing spontaneous curvature and a rolling morphology of the patch (A). Translation to the geometry of a membrane hole (B) where the edge tension τ and the spontaneous curvature c0 acts to create a stable neck conformation. Example of blebbing/folding morphologies induced by ANXA1 and ANXA2 (C) and examples of fluorescence data for patches (POPC: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, POPS: (1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-L-serine), 9:1 ratio, DiDC18) showing blebbing (D) and rolling (E).
Figure 2
Figure 2
Membrane curvature sensing of ANXA2 and ANXA5 measured in lipid nanotubes extracted from Giant Plasma Membrane Vesicles (GPMVs). (A) GPMVs are derived from HEK293T cells expressing ANXA2-GFP or ANXA5-GFP. (B) GFP tagged annexins bind to the inner side of the lipophilic carbocyanine DiD labeled membrane. (C) Images of DiD (red) labeled GPMVs containing ANXA5-GFP (green). (D) Schematic of optical manipulation of the vesicles to form nanotubes with radius ~50nm and length 10µm. (E) Overlay image of a GPMV and nanotube containing GFP tagged ANXA5 and DiD membrane label. (F) Overlay image of a GPMV and nanotube containing GFP tagged ANXA2 and membrane label DiD. (G) Quantification of curvature sorting for ANXA2 and ANXA5, respectively. The dashed line represents Sorting = 1 corresponding to no sorting. *** p = 0.004. (H) The Sorting values from (G) plotted as a histogram which reveals significant heterogeneity in the Sorting by ANXA5. Reproduced with permission from [35].
Figure 3
Figure 3
(A) An overview of the molecular dynamics (MD) procedure, with a simple form of force field and velocity-verlet integration algorithm. The integration timestep in all-atom MD is usually 2 fs. (B) Initial simulation setup of the ANXA4 trimer near a POPC:POPS (4:1) bilayer. (C) Final snapshot showing the indentation of the membrane. (D) Top view of the final snapshot. (E) The 2D curvature profile for a surface passing through the center of the membrane in panel C. (F) Monte-Carlo simulation snapshot of ANXA4 protein affinity for a membrane patch (flat) and a highly curved nanotube generated by pulling a vertex from a flat membrane. Note that the proteins are depicted on the outer surface for clarity.
Figure 4
Figure 4
Plasma membrane injury inflicted by UV-laser ablation injury. (A) Schematic of ablation laser injury to monitor annexin behavior during plasma membrane repair. Ca2+ influx through the wounded membranes activates and enables annexin to bind and seal the hole by bending membrane and glue membrane edges together. (B) Sequential images from time-lapse movie of a MCF-7 breast carcinoma cell showing translocation behavior of ANXA4-RFP to the site of damage (white arrow) upon laser injury.

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