Clathrin-Mediated Endocytosis
| Category | Mechanisms |
|---|---|
| Also known as | CME, clathrin endocytosis |
| Last updated | 2026-04-14 |
| Reading time | 3 min read |
| Tags | mechanismtraffickingmembrane |
Overview
Clathrin-mediated endocytosis (CME) is the best-understood endocytic route and the main mechanism by which cells internalize many nutrient receptors (LDL receptor, transferrin receptor) and signaling receptors (most GPCRs during desensitization, many receptor tyrosine kinases). The pathway is named for clathrin, a triskelion-shaped protein that self-assembles into a polyhedral lattice on the cytoplasmic face of the membrane, deforming it into a coated pit.
CME operates continuously at the plasma membrane. In a typical cell, hundreds to thousands of clathrin-coated pits form, mature, and pinch off per minute. Each pit recruits a defined set of adaptor, accessory, and scission proteins in a stereotyped temporal sequence. The process balances robust selectivity (cargo receptors bear sorting motifs recognized by adaptor proteins) with high throughput.
CME is the canonical example of a vesicle trafficking event and has shaped our understanding of how curved membranes form, how large protein assemblies organize dynamically, and how cells regulate surface receptor populations. It is also a target of infection — many viruses (including influenza, vesicular stomatitis virus, and many others) hijack CME to enter cells.
Mechanism / Process
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Initiation. FCHO1/2 and EPS15 recognize curvature and lipid cues (PI(4,5)P2-rich regions) on the plasma membrane, nucleating a nascent pit.
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Cargo selection. Adaptor protein 2 (AP-2), a heterotetramer, engages cargo through sorting motifs: YxxPhi (tyrosine-based), dileucine motifs, or ubiquitin tags. Alternative adaptors (Epsin, Dab2, Numb, ARH) capture specific cargo classes.
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Clathrin recruitment. AP-2 recruits clathrin triskelia (each composed of three heavy chains and three light chains). Clathrin polymerizes into a hexagonal/pentagonal lattice that deforms the membrane inward.
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Coat maturation. Additional accessory proteins (EPS15, epsin, AP180, intersectin) join the pit. BAR-domain proteins (amphiphysin, endophilin) sense and induce curvature at the pit neck.
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Scission. Dynamin, a large GTPase, assembles a collar at the neck of the invaginated pit. GTP hydrolysis by dynamin drives constriction and membrane fission, releasing the coated vesicle into the cytoplasm.
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Uncoating. Auxilin recruits Hsc70, which uses ATP hydrolysis to disassemble the clathrin cage. The uncoated vesicle fuses with early endosomes (Rab5-positive).
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Downstream sorting. Cargo is sorted for recycling, for continued endosomal signaling, or for lysosomal degradation, as described in endocytosis.
Key Players / Molecular Components
- Clathrin. CHC (heavy chain) and CLC (light chain) forming triskelia.
- AP-2 complex. Alpha, beta2, mu2, sigma2 subunits.
- Accessory adaptors. Epsin, Dab2, Numb, ARH, HIP1.
- BAR-domain proteins. Amphiphysin, endophilin, SNX9.
- Dynamin. Dynamin-1 (neuronal), dynamin-2 (ubiquitous).
- Uncoating. Auxilin, GAK, Hsc70.
Clinical Relevance / Therapeutic Targeting
CME is central to several diseases. Familial hypercholesterolemia results from mutations in the LDL receptor or its adaptor ARH, impairing cholesterol uptake. PCSK9 promotes LDL receptor degradation; anti-PCSK9 antibodies preserve receptor recycling and lower cholesterol. Many viruses and toxins enter cells through CME; pharmacologic inhibitors (dynasore, Pitstop) are research tools. In oncology, internalization kinetics of growth factor receptors (EGFR, HER2) influence response to antibody and small-molecule therapies. Mutations in AP-2 subunits cause developmental disorders, and CME components are emerging drug targets.
Peptides That Target This Pathway
- Transferrin-binding peptides — internalized via CME of transferrin receptor.
- PCSK9-targeting peptides — preserve LDL receptor surface levels by blocking PCSK9 binding.
- GLP-1 analogs — GLP-1R undergoes CME during desensitization.
- Angiotensin II — AT1 receptor internalizes via CME in classical studies.
- Somatostatin analogs — receptor CME used for imaging and radiopeptide therapy.
Related Topics
Related entries
- Receptor Internalization— Receptor internalization is the process by which cell-surface receptors are removed from the plasma membrane via endocytosis, serving as a key mechanism for signal attenuation, receptor recycling, and sustained intracellular signaling.
- Caveolae Endocytosis— A clathrin-independent endocytic pathway using flask-shaped membrane invaginations enriched in caveolin and cholesterol.
- Endocytosis Mechanism— The internalization of extracellular materials, receptors, and membrane components by inward budding of the plasma membrane.
- Receptor Internalization— How cells remove activated receptors from the plasma membrane to desensitize signaling, recycle receptors, or target them for degradation.
- Vesicular Transport— The movement of cargo between intracellular compartments via small membrane vesicles that bud, transit, and fuse in a highly regulated sequence.