Curved membranes are key features of intracellular organelles, and their generation involves dynamic protein complexes. Here we describe the fundamental mechanisms such as the hydrophobic insertion, scaffolding and crowding mechanisms these proteins use to produce membrane curvatures and complex shapes required to form intracellular organelles and vesicular structures involved in endocytosis and secretion. For each mechanism, we discuss its cellular functions as well as the underlying physical principles and the specific membrane properties required for the mechanism to be feasible. We propose that the integration of individual mechanisms into a highly controlled, robust process of curvature generation often relies on the assembly of proteins into coats. How cells unify and organize the curvature-generating factors at the nanoscale is presented for three ubiquitous coats central for membrane trafficking in eukaryotes: clathrin-coated pits, caveolae, and COPI and COPII coats. The emerging theme is that these coats arrange and coordinate curvature-generating factors in time and space to dynamically shape membranes to accomplish membrane trafficking within cells.
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M.M.K. is supported by SFB 958 “Scaffolding of Membranes” (Germany) and Singapore–Israel (NRF-ISF) research grant 3292/19. J.W.T is supported by the Intramural Research Program of the US National Heart, Lung, and Blood Institute, National Institutes of Health. The authors apologize to the many authors whose work could not to be specifically cited in this Review due to space constraints and the long, deep and rich history of this growing and innovative field.
The authors declare no competing interests.
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Flask-shaped nano-structures of plasma membrane rich in proteins, as well as lipids such as cholesterol and sphingolipids, and having several functions in intracellular signal transduction.
A flat cisterna-like membrane compartment serving as a precursor of autophagosome formation.
- Mitochondrial cristae
Folds in the inner membrane of a mitochondrion.
- Receptor expression-enhancing proteins
(REEPs). Proteins belonging to the Yip (Ypt-interacting protein) family and identified by their ability to enhance cell surface expression of a subset of G protein-coupled receptors.
- ENTH domain
The epsin amino-terminal homology domain serving as a structural domain that is found in proteins involved in endocytosis and cytoskeletal machinery.
- BAR domains
Highly conserved protein dimerization domains that occur in many proteins involved in membrane dynamics in a cell. BAR domains are named after three proteins that they are found in: BIN, amphiphysin and Rvs.
A protein involved in membrane trafficking. It is a monomeric small GTPase found in COPII vesicles.
ADP-ribosylation factor involved in protein trafficking among different compartments. It modulates vesicle budding and uncoating within the Golgi complex.
A family of proteins with an amino-terminal transmembrane domain and two cytoplasmic C2 domains. Many C2 domains mediate calcium-dependent binding to negatively charged membranes.
Any derivative of a lipid in which one hydrocarbon chain has been removed by hydrolysis.
- Helfrich model
A theoretical model describing the bending elasticity of lipid membranes. It enables computations of the energy of membrane curvature generation and is based on the concepts of membrane spontaneous curvature and bending moduli.
A family of highly conserved membrane proteins that are important in creating membrane curvature. Epsins contribute to membrane deformations like endocytosis, and block vesicle formation during mitosis.
Clathrin assembly lymphoid myeloid, a member of ANTH-domain containing proteins that promotes clathrin assembly.
A protein that plays an important role in clathrin-mediated endocytosis of synaptic vesicles. It is capable of simultaneously binding both membrane lipids (via an ANTH domain) and clathrin, and is therefore thought to recruit clathrin to the membrane of newly invaginating vesicles.
A dense, gel-like meshwork of glycoproteins and glycolipids that surrounds the cell, constituting a physical barrier for any object to enter the cell.
- Protein condensates
A class of membraneless organelles and organelle subdomains which carry out specialized functions within the cell and which can form through interaction of protein disordered domains.
- Sorting nexins
(SNXs). A large group of proteins that are localized in the cytoplasm and have the potential for membrane association either through their lipid-binding PX domain (a phospholipid-binding motif) or through protein–protein interactions with membrane-associated protein complexes.
Heteropentameric complexes, which in humans are composed of a less defined membrane-associated sorting nexin (SNX) dimer (SNX1, SNX2, SNX5 and SNX6) and a vacuolar protein sorting (VPS) trimer containing VPS26, VPS29 and VPS35.
- Shiga toxins
A family of related toxins with two major groups, Stx1 and Stx2, expressed by genes considered to be part of the genome of lambdoid prophages.
A GTPase responsible for endocytosis in the eukaryotic cell.
The endosomal sorting complexes required for transport (ESCRT) machinery consisting of cytosolic protein complexes, known as ESCRT-0, ESCRT-I, ESCRT-II and ESCRT-III. Together with a number of accessory proteins, these ESCRT complexes enable membrane remodelling that results in membranes bending/budding away from the cytoplasm.
A multimeric protein that works on the cell membrane to internalize cargo in clathrin-mediated endocytosis.
F-BAR domain-only protein 2, a protein that functions in an early step of clathrin-mediated endocytosis.
Epidermal growth factor (EGF) receptor substrate 15, a protein present at clathrin-coated pits in receptor-mediated endocytosis of EGF.
A cytoplasmic membrane-associated protein that indirectly coordinates endocytic membrane trafficking with the actin assembly machinery.
Multifunctional intracellular proteins with an ability to directly interact with a large number of cellular partners.
Disabled 2, a clathrin- and cargo-binding endocytic adaptor protein recognized for its multifaceted roles in signalling pathways.
A component of clathrin-coated pits and vesicles that may link the endocytic machinery to the actin cytoskeleton.
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Kozlov, M.M., Taraska, J.W. Generation of nanoscopic membrane curvature for membrane trafficking. Nat Rev Mol Cell Biol (2022). https://doi.org/10.1038/s41580-022-00511-9