Clathrin-mediated endocytosis

Clathrin-mediated endocytosis

Clathrin-mediated endocytosis (CME) is a major cellular process by which cells internalize molecules (such as nutrients and signaling receptors) from the extracellular space. This process is essential for a variety of cellular functions, including nutrient uptake, receptor downregulation, and synaptic vesicle recycling.

Mechanism

Clathrin-mediated endocytosis begins with the recruitment of clathrin and adaptor proteins to the plasma membrane, forming a clathrin-coated pit. The clathrin triskelion, composed of three clathrin heavy chains and three light chains, assembles into a basket-like structure that helps to invaginate the membrane.

1. Initiation: The process is initiated by the binding of adaptor proteins, such as AP-2, to specific phospholipids and cargo receptors on the plasma membrane. These adaptors recruit clathrin to the site of endocytosis.

2. Coat Assembly and Cargo Selection: Clathrin and adaptor proteins form a lattice on the cytoplasmic side of the membrane, selecting and concentrating cargo molecules into the forming vesicle.

3. Membrane Invagination: The clathrin coat induces curvature in the membrane, leading to the invagination of the clathrin-coated pit.

4. Vesicle Scission: The GTPase dynamin wraps around the neck of the invaginated pit and, upon GTP hydrolysis, constricts to sever the vesicle from the plasma membrane.

5. Uncoating: After the vesicle is released into the cytoplasm, the clathrin coat is rapidly disassembled by the action of Hsc70 and auxilin, allowing the vesicle to fuse with early endosomes.

Functions

Clathrin-mediated endocytosis is involved in numerous cellular processes, including:

• Nutrient Uptake: Internalization of essential nutrients such as iron and cholesterol via transferrin and LDL receptors, respectively.
• Receptor Downregulation: Removal of activated receptors from the cell surface to terminate signaling, such as the internalization of EGF receptors.
• Synaptic Vesicle Recycling: In neurons, CME is crucial for the recycling of synaptic vesicles after neurotransmitter release.

Clinical Significance

Defects in clathrin-mediated endocytosis can lead to various diseases, including neurodegenerative disorders, cancer, and cardiovascular diseases. For example, mutations affecting the function of dynamin are linked to certain forms of Charcot-Marie-Tooth disease.

Also see

• Endocytosis
• Clathrin
• Dynamin
• Adaptor protein complex 2
• Synaptic vesicle