Dynamic Shaping of Cellular Membranes by Phospholipids and Membrane-Deforming Proteins

Abstract

All cellular compartments are separated from the external environment by a membrane, which consists of a lipid bilayer. Subcellular structures, including clathrin-coated pits, caveolae, filopodia, lamellipodia, podosomes, and other intracellular membrane systems, are molded into their specific submicron-scale shapes through various mechanisms. Cells construct their micro-structures on plasma membrane and execute vital functions for life, such as cell migration, cell division, endocytosis, exocytosis, and cytoskeletal regulation. The plasma membrane, rich in anionic phospholipids, utilizes the electrostatic nature of the lipids, specifically the phosphoinositides, to form interactions with cytosolic proteins. These cytosolic proteins have three modes of interaction: 1) electrostatic interaction through unstructured polycationic regions, 2) through structured phosphoinositide-specific binding domains, and 3) through structured domains that bind the membrane without specificity for particular phospholipid. Among the structured domains, there are several that have membrane-deforming activity, which is essential for the formation of concave or convex membrane curvature. These domains include the amphipathic helix, which deforms the membrane by hemi-insertion of the helix with both hydrophobic and electrostatic interactions, and/or the BAR domain superfamily, known to use their positively charged, curved structural surface to deform membranes. Below the membrane, actin filaments support the micro-structures through interactions with several BAR proteins as well as other scaffold proteins, resulting in outward and inward membrane micro-structure formation. Here, we describe the characteristics of phospholipids, and the mechanisms utilized by phosphoinositides to regulate cellular events. We then summarize the precise mechanisms underlying the construction of membrane micro-structures and their involvements in physiological and pathological processes.

Protein kinase C (PKC)-mediated phosphorylation of PACSIN2 triggers the removal of caveolae from the plasma membrane

“…Our group and others have shown that PACSIN2 localizes to and functions at caveolae (Hansen et al, 2011;Koch et al, 2012;Senju et al, 2011). Moreover, BAR domain proteins are known to bind to negatively-charged lipids, including phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P 2 ] (Suetsugu et al, 2014), and PtdIns(4,5) P 2 is enriched at caveolae (Fujita et al, 2009). S313 phosphorylation caused a decrease in the membrane-binding and tubulation abilities of PACSIN2.…”

“…Proteins containing a membrane-sculpting Bin-Amphiphysin-Rvs (BAR) domain are evolutionarily conserved, and members of this family are found at various intracellular membrane structures, including clathrin-coated pits, compartments of the endocytic pathways, and membrane protrusions, such as filopodia and lamellipodia (Safari and Suetsugu, 2012;Suetsugu et al, 2014). BAR domain proteins form crescent-shaped homodimers and sense or generate membrane curvature through positively charged surfaces (Frost et al, 2008(Frost et al, , 2009Itoh and De Camilli, 2006;Peter et al, 2004;Suetsugu et al, 2010), thereby performing crucial roles in membrane remodeling.…”

Different functional modes of BAR domain proteins in formation and plasticity of mammalian postsynapses

“…Recently, an increasing number of loss-of-function studies has addressed whether these observations have any cell biological or physiological importance. These analyses indeed frequently reveal phenotypes in endocytosis and/or neuronal morphology establishment -processes that involve extensive and spatially restricted changes in membrane topology Suetsugu et al, 2014) -thereby suggesting that BAR domain proteins are indeed crucial for shaping membranes in vivo (Fig. 3A).…”

“…Most BAR domain proteins have the ability to shape liposomes and many have also been reported to overcome the membrane tensions of living cells and to form tubules or membrane protrusions upon their overexpression Qualmann et al, 2011;Mim and Unger, 2012;Suetsugu et al, 2014). Recently, an increasing number of loss-of-function studies has addressed whether these observations have any cell biological or physiological importance.…”

Ultrastructural Aspects of Rat Renal Tubular Epithelium <i>in Vitro</i>: Scanning Electron Microscopy （SEM） Analyses at Various Stages of Culture

“…3A, B, C . Lamellipodia are defined as the thinner regions located at the cell periphery where the actin fiber is much denser than in the remainder of the cell 9,[22][23][24] . However, in the lamellipodia definition, cellular polarity is not necessarily taken into account.…”