Clathrin proteins involved in endocytosis form a lattice that can dramatically change its shape to form the vesicle. [Ori Avinoam/EMBL]
Clathrin proteins involved in endocytosis form a lattice that can dramatically change its shape to form the vesicle. [Ori Avinoam/EMBL]

The formation of clathrin-coated pits that surround endocytic vesicles are among some the basic mechanisms taught in cell biology. Moreover, these structures were amid some of the first described by electron microscopy over 50 years ago. However, despite these processes and structures being well studied for decades, the precise mechanisms of vesical formation has eluded scientists and bifurcated opinions on the matter.

Endocytosis is the absorption route cells use to engulf large molecules and draw them within the cytoplasm. The engulfment mechanism involves invagination of the cell membrane, which deepens over time and eventually seals off, forming a spherical vesicle within the cell. Essential to the process is the formation of a clathrin shell on the surface of the vesicle membrane. However, there has been little consensus as to the exact function of this coat, and hypotheses are split between two different models.

In the first model, the clathrin coat assembles as a flat structure and then bends, essentially wrapping around the forming vesicle. The second model suggests that clathrin assembles directly, assuming the shape of the membrane as it is drawn inward.  

Although the second model has been more generally accepted, new research from scientists at the European Molecular Biology Laboratory (EMBL) in Heidelberg describes the first model as being more accurate. The EMBL scientists utilized human cell lines that had been tagged with fluorescent markers on sites where endocytosis occurs. Additionally, the researchers used 3D electron tomography to locate endocytic sites and determine their coat and membrane shapes during invagination. 

“Our results were surprising because the proteins have to undergo some complicated geometric transformations to go from a flat to a curved shape, which is why the second model was favoured by scientists for such a long time,” explained John Briggs, Ph.D., group leader and senior scientist at EMBL Heidelberg and co-author on the current study.

The findings from this study were published recently in Science through an article entitled “Endocytic sites mature by continuous bending and remodeling of the clathrin coat.”

The investigators found that by using computational analysis for the captured images, they were able to demonstrate that the surface area of the clathrin coat does not change during endocytosis. They found that the coat changes only its curvature as it draws the cell membrane inward.

The EMBL scientists were excited about their findings because they suggest answers to longstanding questions about the molecular underpinnings surrounding the formation and structure of endocytic vesicles. Yet, the researchers realize that their results are preliminary and that more questions remain to be answered.

“The next stage of our research is to investigate more precisely how this rearrangement occurs,” stated Marko Kaksonen, Ph.D., visiting group leader at EMBL Heidelberg and senior author on the current study. “We also want to look at other aspects of the process, such as how the molecules ingested by the cells might themselves influence the action of the clathrin proteins. Answering these fundamental questions of cell biology will help scientists better understand the whole process of endocytosis.”

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