The clathrin protein is a fundamental component found within the cells of all eukaryotes, which include animals, plants, and fungi. It serves as a specialized protein responsible for packaging various materials into small, membrane-bound sacs known as vesicles. Its primary function involves forming a temporary “coat” around these vesicles, ensuring their proper formation and transport.
The Unique Structure of Clathrin
Clathrin is recognized for its unique three-legged shape, often referred to as a “triskelion.” Its three individual “legs” radiate from a central point. Each of these “legs” is composed of two distinct protein components: a larger clathrin heavy chain, which provides the main structural backbone, and a smaller clathrin light chain, which is tightly associated with the heavy chain. The light chains help regulate the assembly and disassembly of the clathrin structure.
The heavy chain is extended and comprised of several domains. The light chains bind to the heavy chain, contributing to the overall stability and function of the triskelion.
Forming Cages for Cellular Transport
Clathrin’s primary and most studied function involves a process called clathrin-mediated endocytosis (CME), which allows cells to internalize substances from their external environment. This process begins when clathrin triskelions are recruited to specific sites on the cell membrane, often with the assistance of adaptor proteins, which link clathrin to the membrane and its cargo. Once recruited, these triskelions interlink and self-assemble into a polyhedral lattice, forming a dome-like or soccer ball-shaped structure on the inner surface of the membrane. This assembly gradually pulls the cell membrane inward, creating a characteristic depression known as a “coated pit.”
As the coated pit deepens, it concentrates specific molecules or “cargo” destined for internalization. The continued growth and curvature of the clathrin lattice drive the invagination of the membrane. Once the pit has formed a deep, constricted neck, another protein, a large GTPase called dynamin, assembles around this neck. Dynamin then undergoes a conformational change, powered by the hydrolysis of GTP, which causes it to constrict and “pinch off” the nascent vesicle from the main cell membrane. This action releases a newly formed “clathrin-coated vesicle” (CCV) into the cell’s cytoplasm.
Immediately after budding, the clathrin coat rapidly disassembles in a process called “uncoating,” which is facilitated by the ATPase chaperone Hsc70 and its cofactor auxilin. This uncoating step is necessary because it allows the vesicle to fuse with other cellular compartments and deliver its contents, while the disassembled clathrin components can be recycled for future vesicle formation.
Diverse Roles in Cellular Processes
Clathrin’s contributions extend beyond merely bringing substances into the cell from the outside. Within the cell, it plays a role at the trans-Golgi network (TGN), which is the final sorting station of the Golgi apparatus. Here, clathrin, often in conjunction with adaptor protein complexes like AP-1 and GGA proteins, helps to sort and package newly synthesized proteins and lipids into vesicles. For example, it helps to direct lysosomal enzymes, which are tagged with mannose-6-phosphate receptors, into clathrin-coated vesicles for transport to endosomes and ultimately to lysosomes, where they perform degradative functions.
Beyond its involvement in membrane trafficking, clathrin also participates in cell division, a process known as mitosis. During mitosis, clathrin’s traditional vesicle-forming activity is largely shut down, and it instead localizes to the mitotic spindle apparatus. Here, clathrin, in a complex with other proteins like TACC3 and ch-TOG, helps to stabilize the kinetochore fibers of the mitotic spindle. This stabilization is important for the proper alignment and segregation of chromosomes to daughter cells, ensuring that each new cell receives a complete set of genetic material.
Clathrin’s Connection to Health and Disease
The involvement of clathrin in fundamental cellular processes means that its dysfunction or manipulation can have significant implications for human health. Many viruses, including influenza A, hepatitis C virus, and even SARS-CoV-2, exploit the clathrin-mediated endocytosis pathway to gain entry into host cells. These viruses hijack the cell’s own machinery, binding to cell surface receptors and triggering their internalization via clathrin-coated vesicles, allowing the viral particles to be transported into the cytoplasm. Once inside, the viruses can then escape the endosomal compartments to initiate their replication.
In the nervous system, clathrin’s role in recycling synaptic vesicles is particularly important. Neurotransmission, the process by which nerve cells communicate, relies on the rapid release and subsequent retrieval of these vesicles at synapses. Clathrin-mediated endocytosis is the main mechanism for this continuous recycling, ensuring a ready supply of vesicles for neurotransmitter release. Defects in this process can disrupt synaptic function and have been linked to various neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, epilepsy, and schizophrenia, where altered clathrin-dependent vesicle recovery can compromise neuronal communication.
Furthermore, altered clathrin activity can be observed in cancer. Clathrin-mediated endocytosis regulates the internalization of cell-surface receptors, which in turn influences downstream signaling pathways involved in cell growth, proliferation, and metastasis. Changes in clathrin-mediated endocytosis can lead to dysregulated trafficking of receptors, such as epidermal growth factor receptors (EGFRs), affecting their signaling and contributing to enhanced cancer cell migration and proliferation. Some studies indicate that the expression of certain clathrin components, like the clathrin light chain b isoform, is altered in specific cancers, impacting cell behavior.