Molecular mechanism and physiological functions of clathrin-mediated endocytosis

Key Points

  • Clathrin-mediated endocytosis is a modular process, in which the different stages of cargo collection and vesicle formation are made up of protein modules. An understanding of these modules facilitates a molecular description of the pathway.

  • The distinct modular nature allows for some clathrin modules to be used in non-clathrin pathways or additional modules to be used in variations of the clathrin pathway. This sometimes makes for ambiguity in the definition of the fundamental nature of the pathway.

  • The modular nature allows for adaptability, as the cargo selection can be fine-tuned in various tissues, for example by the addition of cargo-specific adaptor proteins. The concentration of different cargoes in a single vesicle, by using a wide range of cargo-specific adaptor proteins, allows the building of a complex vesicle by this process. For example, a synaptic vesicle formed by clathrin-mediated endocytosis can have over 20 different cargoes in specific stoichiometries.

  • By controlling the specific turnover of proteins deposited in the plasma membrane, clathrin-mediated endocytosis plays a fundamental part in signalling, cell motility, cell–cell communication and cell fate, and can be 'hijacked' by many human pathogens.

  • Although mutations are found in the clathrin-mediated endocytosis pathway, they tend to concentrate on non-essential (non-hub) components, as loss of the function of key components is embryonic lethal.

Abstract

Clathrin-mediated endocytosis is the endocytic portal into cells through which cargo is packaged into vesicles with the aid of a clathrin coat. It is fundamental to neurotransmission, signal transduction and the regulation of many plasma membrane activities and is thus essential to higher eukaryotic life. Morphological stages of vesicle formation are mirrored by progression through various protein modules (complexes). The process involves the formation of a putative FCH domain only (FCHO) initiation complex, which matures through adaptor protein 2 (AP2)-dependent cargo selection, and subsequent coat building, dynamin-mediated scission and finally auxilin- and heat shock cognate 70 (HSC70)-dependent uncoating. Some modules can be used in other pathways, and additions or substitutions confer cell specificity and adaptability.

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Figure 1: Clathrin-dependent and -independent internalization pathways.
Figure 2: The clathrin-coated vesicle cycle.
Figure 3: Species variations and physiological functions of clathrin-mediated endocytosis.

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Acknowledgements

We thank M. Robinson and R. Mittal for critical reading of the manuscript. H.T.M. and E.B. are supported by the Medical Research Council, UK.

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Glossary

Adaptor proteins

Proteins linking receptors to clathrin triskelia.

Triskelia

Shapes that consists of three bent limbs radiating from a centre.

Module

A set of proteins working together to carry out a specific function.

F-BAR domain

FES–CIP4 homology (FCH) Bin–amphiphysin–Rvs (BAR) domain.

Synapses

Specialized junctions between cells that allow neurons to transmit chemical signals to other cells (neural or otherwise).

SNARE proteins

(Soluble NSF (N-ethylmaleimide-sensitive factor) attachment protein receptor proteins). Members of a family of membrane-tethered coiled-coil proteins that regulate fusion reactions and target specificity. On the basis of their localization, they can be divided into vesicle membrane SNAREs (v-SNAREs) and target membrane SNAREs (t-SNAREs).

G protein-coupled receptors

(GPCRs; also known as seven transmembrane domain receptors). The largest family of cell surface receptors (>800 members) that sense molecules outside the cell and activate signal transduction pathways.

Phagocytosis

A specific form of endocytosis involving the internalization of solid particles, such as bacteria.

Vacuole

A membrane-bound organelle that is present in all plant and fungal cells, as well as in the cells of some other organisms. It is the equivalent to the lysosomes in other organisms.

GPI-anchored protein

A protein anchored by glycosylphosphatidylinositol (GPI) in the secretory pathway to reach the extracellular leaflet of the plasma membrane.

Fluid-phase uptake

(Also called macropinocytosis). Endocytosis of large (0.5–5 mm diameter) vesicles derived from ruffling of the plasma membrane, taking up extracellular fluid in a nonspecific manner.

α-factor

A yeast mating pheromone that is recognized by the receptor Ste2.

Neurotransmitters

Endogenous molecules that transmit signals from a neuron to a target cell across a synapse.

Exocytosis

The process by which the content of secretory vesicles (such as a synaptic vesicle) is released out of the cell.

Fc receptor

A surface molecule found on various cells that binds to the crystallizable fragment (Fc) regions of immunoglobulins, thereby initiating immune effector functions.

Somatic mutations

Mutations, or change in genomic sequence, happening in somatic cells (thus, non-inheritable).

Multiploidy

An abnormal number of chromosomes (>2n), usually the result of defective cell division.

Single nucleotide polymorphisms

DNA sequence variations occurring when a single nucleotide differs between paired chromosomes in an individual or between members of a biological species.

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McMahon, H., Boucrot, E. Molecular mechanism and physiological functions of clathrin-mediated endocytosis. Nat Rev Mol Cell Biol 12, 517–533 (2011). https://doi.org/10.1038/nrm3151

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