Clathrin-mediated endocytosis (CME). Sounds like a bunch of gibberish right? I mean, clathrin sounds like a name… Katherine? Surely, you just made that up, you might be thinking. Well, not surprisingly, it does mean something; lets break it down one word at a time. Endocytosis is the process by which a cell intakes outside materials. You want to be thinking of an amoeba feeding: surrounding its prey and then swallowing it whole, though this is a very simplified analogy. There are a lot of different processes to take in materials, one of which is CME, a process used by the cell to internalize metabolites, hormones, and proteins (ligands) from the extracellular space by budding the cell membrane inward. CME is initiated by the ligand binding to a receptor on the cell surface; binding of clathrin on the inside part of the receptor initiates budding and allows entry.
Lets change the analogy up a little: imagine a castle with high walls, and a massive lumbering gate. Only permission from the king will allow entry into the castle. Here, the castle gate and wall is the cell membrane, the king sending guards to the gate keeper is clathrin, and the gatekeeper is the receptor. When a traveller (metabolite) approaches the gate (cell membrane) and asks for entry (binding of the metabolite to the receptor), the gatekeeper sends a message to the king to ask for permission to open the gate (signaling for clathrin to the plasma membrane). If the king grants permission and sends guards to the gate (arrival of clathrin to the cell membrane), the gatekeeper opens the gate and allows the traveller in (curving of the plasma membrane and ultimately, endocytosis). Sometimes, the king grants permission, but changes his mind shortly after. Here the gate opens halfway, and then slams shut. This often occurs with clathrin-mediated endocytosis: 60% of clathrin endosomes are abortive.
The point of this article review is not to discern the research in Miller et al. (2015) article, but to understand that research often involves revisiting previous conclusions. CALM is a protein involved in membrane curvature: it binds to the plasma membrane of the cell to cause the membrane to curve inward during CME, and to sense curvature caused by other cellular components. At a certain point, the curvature point of no return is hit, signaling for the endosome to bud off and enter the cell. In order for a protein to detect changes in membrane curvature, it needs one of two protein domains: either a BAR domain or an amphipathic helix. The issue is, previous research had shown that CALM did not contain either of those structural elements. Thirteen years after scientists came to that conclusion that CALM lacked these domains, new analysis methods have shown that CALM does indeed contain an amphipathic helix – and that it is responsible for causing, and detecting, membrane curvature. With science, nothing is ever completely in stone – theories are disproven constantly and that’s the point of the scientific method: aim to disprove rather than prove.
Miller, S. E., Mathiasen, S., Bright, N. A., Pierre, F., Kelly, B. T., Kladt, N., … Owen, D. J. (2015). CALM Regulates Clathrin-Coated Vesicle Size and Maturation by Directly Sensing and Driving Membrane Curvature. Developmental Cell, 33(2), 163–175. doi:10.1016/j.devcel.2015.03.002