Clathrin and Clathrin-Adaptors

Introduction to Clathrin and Clathrin-Adaptors

Endocytosis is an important cellular process in neuro signal transmission between neurons. Receptor-mediated endocytosis is a major endocytic form in mammalian cells mediated by clathrin protein, which is also named clathrin-mediated endocytosis.

Clathrin is a self-assembling protein identified by Roth and Porter in 1976, which has been indicated to exert an essential role in the formation of coated vesicles. During the process of clathrin-coated vesicle formation, clathrin adaptor proteins, also known as adaptins, are responsible for linking clathrin proteins to the cytoplasmic domain of the receptor on the surface of the coated vesicle. In addition to the involvement in endocytosis, clathrin proteins also have been demonstrated to play a critical role in mitosis.

Structures of Clathrin and Clathrin-Adaptors

Clathrin is a highly conserved protein, which consists of three clathrin heavy chains and three light chains. Each heavy chain and light chain form a dimer, and three dimers form the basic structural unit of the coating-triskelion, which is also named as three-legged protein. The three heavy chains of clathrin, described as legs, radiate from a central vertex consisting of three domains, a proximal domain close to the vertex for the binding of the light chain, a distal domain, and an N-terminal domain. The N-terminal domain of the heavy chain is globular and has a seven-bladed β-propeller structure, whereas the other domains present a right-handed superhelix of short α-helical zigzags. The light chain of clathrin containing a linear array of domains, has two isoforms, light chain a and light chain b. In clathrin triskelion, the heavy chains are mainly responsible for providing the structural backbone of the clathrin lattice, while the light chains are essential to regulate the formation and disassembly of a clathrin lattice.

Clathrin adaptors are heterotetrameric complexes consisting of four different subunit chains. There are four adaptor proteins (APs) that have been identified in mammalian cells, namely AP-1, AP-2, AP-3, and AP-4. These APs interact with clathrin through binding to the β-propeller at the N-terminus of the clathrin heavy chain, by which they facilitate clathrin assembly.

Fig.1 Structure and function of clathrin and clathrin adaptor proteins. (Gwendolyn, 2019)

Functions of Clathrin and Clathrin-Adaptors in Endocytosis

Generally, receptor-mediated endocytosis is roughly summarized in 6 steps, that are initiation, growth, stabilization, vesicle budding, scission, and uncoating. Both clathrin and clathrin adaptor proteins are involved in almost the whole process of receptor-mediated endocytosis, especially performs critical roles in the formation of coated vesicles in the cytoplasm for intracellular trafficking.

Once the cargo ligands binding to the cell membrane receptors, receptor-mediated endocytosis is initiated. Then the cargo ligand-receptor complex recruits clathrin adaptor proteins (AP2) or clathrin associated sorting proteins (CLASPs) at the intracellular side of the plasma membrane. Subsequently, the complex recruits clathrin triskelions to form a budding (then a clathrin-coated pit) on the plasma membrane, initiate vesicle assembly. When the pit matures and fuses with the plasma membrane, fission proteins such as dynamin function to detach the pit from the membrane, forming the clathrin-coated vesicle. The intracellular clathrin-coated vesicle is then uncoated, releasing a free vesicle that fuses with a target endosome.

Fig.2 Mechanism of clathrin-dependent endocytosis.

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Reference

1. Gwendolyn, M.; et al. Conformational regulation of AP1 and AP2 clathrin adaptor complexes. Traffic (Copenhagen, Denmark). 2019, 20(10): 741-751.