Clathrin-Mediated Endocytosis Mechanisms and Dynamics

Clathrin-mediated endocytosis (CME) is the principal pathway by which eukaryotic cells internalise receptors, nutrients and signalling molecules from the plasma membrane. The process begins with recruitment of adaptor complexes, primarily AP2, to phosphoinositide-rich membrane domains. These adaptors recognise specific cargo motifs and nucleate assembly of triskelion-shaped clathrin units into a polyhedral lattice. Progressive polymerisation of clathrin induces membrane curvature, forming a clathrin-coated pit (CCP). Accessory proteins such as epsins, CALM and BAR-domain factors sculpt the growing bud, while actin filaments often provide additional force in regions of high membrane tension or rigid cortical cytoskeleton. At a late stage, dynamin oligomerises around the narrow neck of the pit and, through GTP hydrolysis, catalyses scission of the vesicle from the parent membrane. The freed clathrin coat then disassembles, driven by auxilin and Hsc70, allowing receptor recycling and coat component recovery. Recent work has revealed dynamic equilibria among adaptor–clathrin interaction sites, new membrane-tension checkpoints governing coat geometry, and unanticipated roles for clathrin itself in membrane fission. Together, these advances outline a modular yet highly flexible pathway in which cargo selection, membrane mechanics and protein dynamics converge to regulate vesicle size, lifetime and fate.

Research from Nature Portfolio

High-resolution spectroscopic studies have uncovered an extended, high-affinity binding site in the neuronal adaptor AP180 that engages AP2 in a dynamic equilibrium. Atomic-level analysis shows this 70-residue segment drives initial adaptor clustering on the membrane, while flanking weaker sites stabilise recruitment under elevated AP2 concentrations, suggesting a multivalent code for nucleation of clathrin-coated structures. Complementary in vitro reconstitution of clathrin budding on giant vesicles has enabled quantitative mapping of how membrane tension opposes clathrin polymerisation. Under low tension, coats bud extensively into spherical vesicles, whereas moderate tension yields shallow pits and high tension halts polymer assembly altogether. Theoretical modelling predicts tension thresholds for these transitions and permits estimation of clathrin polymerisation energy. Another foundational contribution demonstrated that large intrinsically disordered regions of adaptor proteins, lacking classical curvature motifs, generate steric pressure to bend membranes. These disordered–domain experiments reveal that membrane curvature can emerge from hydrodynamic exclusion forces, broadening our understanding of how diverse adaptors participate in early pit formation.

Clathrin-Mediated Endocytosis Mechanisms and Dynamics publication trend

The graph below shows the total number of articles in clathrin-mediated endocytosis mechanisms and dynamics across all publications each year (not limited to Nature Index journals).

Technical terms

Clathrin-coated pit (CCP): A membrane invagination formed by polymerisation of clathrin triskelia around selected cargo and adaptor proteins.

Adaptor protein 2 (AP2): A heterotetrameric complex that links transmembrane cargo motifs to clathrin and organises early stages of pit assembly.

Intrinsically disordered region (IDR): A protein segment lacking fixed tertiary structure that can drive membrane curvature through steric pressure.

Membrane tension: The lateral force within the lipid bilayer that opposes deformation and influences the energetics of coat assembly.

Scission: The final cleavage event that separates a coated vesicle from the plasma membrane, completing endocytic uptake.

References

1. An extended interaction site determines binding between AP180 and AP2 in clathrin mediated endocytosis. Nature Communications (2024).
2. A balance between membrane elasticity and polymerization energy sets the shape of spherical clathrin coats. Nature Communications (2015).
3. Intrinsically disordered proteins drive membrane curvature. Nature Communications (2015).
4. Clathrin mediates membrane fission and budding by constricting membrane pores. Cell Discovery (2024).
5. A High Precision Survey of the Molecular Dynamics of Mammalian Clathrin-Mediated Endocytosis. PLOS Biology (2011).