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The word clathrin originates from the Latin word clāthrāre, meaning “to provide with a lattice”. Clathrin is a protein involved in receptor-mediated endocytosis.1 It was not discovered until 1975 by Barbara Pearse, a British biological scientist. Clathrin is a protein resembling a triskelion shape and is composed of three heavy chains and three light chains which come together to form a polyhedral lattice similar to a cage. The three heavy chains resemble three legs protruding from a center point. Some of the major functions of clathrin include lysosomal targeting, receptor-mediated endocytosis, and organelle biogenesis from the trans-Golgi network.3 The polyhedral lattice shape of clathrin largely determines its functionality, in that there are many binding sites for proteins on the heavy chains of the lattice as well.4

Structure

Individual Clathrin Molecule

An individual clathrin molecule is composed of three heavy chains, each being attached to a light chain. This structure is often referred to as a triskelion shape.1 The heavy chains of clathrin are made of an amino-terminal, a beta-propellor domain containing multiple repeats of the WD40 binding motif, alpha-helical zig-zags close to 30 amino acids in length, a lengthened alpha-helix where the threefold contacts, and a carboxy-terminal.1 The aforementioned zig-zags are what create the “leg” looking structure of the triskelion. 1

Part of the heavy chain is designated to bind to the light chains, of which there are two variations in mammals. The heavy chain and light chain bind through one long alpha helix towards the center of the protein. 1

Clathrin Lattice

Individual clathrin molecules can assemble into cage-like structures. When individual clathrin molecules come together, a lattice is formed where each lattice point is associated with the center of a triskelion (from the Greek word meaning “a three legged structure”).1

Functions

Endocytosis

The formation of most cellular vesicles are facilitated by coat-proteins like clathrin.2 Endocytic events are initiated through the activity of the clathrin coat and adaptor proteins that select the “cargo” that will be carried into the cell in vesicles.7 Cells endocytose vesicles from the plasma membrane to perform housekeeping tasks such as taking up nutrients, importing signaling receptors, mediating immune responses, cleaning up cell debris, or providing a pathway for pathogens or toxins.2

Canonical and Non-canonical Pathway

The canonical clathrin pathway is referred to as the clathrin coated pits and the coated vesicles of endocytosis, whereas the noncanonical clathrin pathway is related to the clathrin-actin assembles of phagocytotic processes.1

Classical endocytosis involving clathrin-coated pits and clathrin-coated vesicles is referred to as the canonical clathrin pathway.9 Canonical clathrin-dependent pathways involve the uptake of transferrin (Tf) by transferrin receptor (TfR) and the uptake of LDL by LDL receptors (LDLR).1 Early studies showed that LDL epidermal growth factor (Tf) bound to their specific receptors could be endocytosed within the same vesicle.9 The receptors for these molecules are composed of tails on their cytoplasmic side that contain sequences, which determine cargo sorting and also signal for clathrin to bind.9 Clathrin then coats these vesicles and endocytosis occurs.9 Other pathways, such as reuptake of neurotransmitters into the synaptic cleft, are seen to have similar mechanisms to canonical clathrin pathways.9

The clathrin-actin assembly forms phagocytotic vesicles in response to invading bacterium.9 Pathogen invasion into nonphagocytic cells result in the recruitment of clathrin.1 These pathogens invade the cell through a process called the “zippering” mechanism, in which actin filaments are utilized to surround the pathogens with the host-cell membrane.1

Relevance

Structural highlights

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