Curvature of clathrin-coated pits driven by epsin
Abstract
Clathrin-mediated endocytosis involves cargo selection and membrane budding into vesicles with the aid of a protein coat. Formation of invaginated pits on the plasma membrane and subsequent budding of vesicles is an energetically demanding process that involves the cooperation of clathrin with many different proteins. Here we investigate the role of the brain-enriched protein epsin 1 in this process. Epsin is targeted to areas of endocytosis by binding the membrane lipid phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P(2)). We show here that epsin 1 directly modifies membrane curvature on binding to PtdIns(4,5)P(2) in conjunction with clathrin polymerization. We have discovered that formation of an amphipathic alpha-helix in epsin is coupled to PtdIns(4,5)P(2) binding. Mutation of residues on the hydrophobic region of this helix abolishes the ability to curve membranes. We propose that this helix is inserted into one leaflet of the lipid bilayer, inducing curvature. On lipid monolayers epsin alone is sufficient to facilitate the formation of clathrin-coated invaginations.
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Clathrin-adaptor proteins such as AP2 complex and monomeric adaptors including CALM/PICALM family and epsins bind to cargo molecules and lipids in plasma membrane.
“A recent report revealed that the clathrin-adaptor proteins such as the heterotetrametric adaptor protein AP2 complex and monomeric adaptors including lymphoid myeloid leukemia protein (CALM, known as PICALM) family and epsins, which are proteins of the clathrin assembly, bind to cargo molecules and lipids in the plasma membrane [52,53,54].”
From Insights of Endocytosis Signaling in Health and Disease (2023) · cites this paper as [53]
The first alpha helix (α0) of the N-terminal ENTH domain can insert into the membrane and induce curvature formation.
“In addition, the first alpha helix (α0) of the N-terminal ENTH domain can insert into the membrane and induce curvature formation (Fig. 4a)89,90 – this function of Epsin1 is thought to be important for endocytosis.”
From Membrane compression by synaptic vesicle exocytosis triggers ultrafast endocytosis (2023) · cites this paper as [90]
After clathrin recruitment, PI(4,5)P2 facilitates membrane deformation; epsin binds PI(4,5)P2 and inserts an amphipathic helix, and BAR domain proteins also contribute.
“After clathrin recruitment, PI(4,5)P2 facilitates membrane deformation. Epsin binds to PI(4,5)P2, localising epsin to the endocytic site where it inserts an amphipathic helix for membrane deformation [101,102]. Accessory proteins with BAR (domain named after three proteins: Bin, Amphiphysin and Rvs that share the domain) domains, which also bind PI(4,5)P2, also contribute to deformation of the”
From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [102]
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- Authors
- Ford, M. G. J., Mills, I. G., Peter, B. J., Vallis, Y., Praefcke, G. J. K., Evans, P. R., & McMahon, H. T.
- Affiliations
- MRC Laboratory of Molecular Biology (GB)
- Corresponding author
- Evans, Philip R.
- McMahon, Harvey T.
- Venue
- Nature
- Published
- 2002-09
- Volume
- 419
- Issue
- 6905
- Pages
- 361-366
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2114628856
- Cited by
- 1,019
- References
- 0
- Citations by year
- 2026: 10 · 2025: 23 · 2024: 29 · 2023: 26 · 2022: 39 · 2021: 48 · 2020: 36 · 2019: 42 · 2018: 35 · 2017: 33 · 2016: 48 · 2015: 39 · 2014: 46 · 2013: 39 · 2012: 61
- FWCI
- 20.29
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Research Portal (Queen's University Belfast) (submittedVersion)
- Funders
- European Synchrotron Radiation Facility
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Caveolin-1 and cellular processes
- Keywords
- clathrin, membrane curvature, clathrin-mediated endocytosis, phosphatidylinositol 4,5-bisphosphate, amphipathic helix, lipid bilayer insertion, membrane invagination, vesicle budding, lipid monolayers
- MeSH terms
- Amino Acid Sequence, Animals, Biopolymers, Brain, Carrier Proteins, Clathrin, Coated Pits, Cell-Membrane, Drosophila melanogaster, Endocytosis, Humans, Liposomes, Membrane Proteins, Microscopy, Electron, Models, Molecular, Molecular Sequence Data, Mutation, Neuropeptides, Protein Binding, Inositol 1,4,5-Trisphosphate, Protein Structure, Tertiary, Crystallography, X-Ray, Phosphatidylinositol 4,5-Diphosphate, Vesicular Transport Proteins, Adaptor Proteins, Vesicular Transport, Rats
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