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Cell Vesicles Wear Sophisticated Coats

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Envision a day when self-driving cars make driving obsolete. Now, imagine a far-future day when you don’t even have to get in the car. Instead, as you walk out the front door, a car assembles around you, lifts off the ground, floats you to your destination, then disassembles in anticipation of picking up the next passenger. Something like this actually happens in living cells. According to news from the European Molecular Biology Laboratory (EMBL):

Researchers at EMBL Heidelberg have produced detailed images of the intricate protein-coats that surround trafficking vesicles — the “transport pods” that move material around within biological cells. The study, published today in Science, provides a new understanding of the complex machines that make up the cells’ logistics network.

Vesicles are responsible for transporting molecules between the different compartments within a cell and also for bringing material into cells from outside. There are several types of vesicle: each has a specific type of coat which is made up of different proteins and assembles onto a membrane surrounding the vesicle. [Emphasis added.]

There are three models of “transport pods” that molecular biologists know about, each with its own specific coat proteins: Coat Protein 1 (COPI), Coat Protein 2 (COPII), and clathrin-coated vesicle (CCV). Each coat has its own proteins, adaptors, and functions. The first paper in Science looks in detail at COPI; but first, let’s mention COPII. This type of vesicle takes proteins from the endoplasmic reticulum (ER), where they were assembled, to the Golgi apparatus where they will be packaged for delivery. This is called anterograde (forward) transport.

COPI is the reverse; it takes proteins from the Golgi back to the ER, or to different compartments of the Golgi. This is called retrograde (backward) transport. Surprisingly, the coat proteins on these vesicles are very different. COPII coats are made of four proteins that assemble with four-fold symmetry in a sequential manner, using separate adaptor proteins. COPI is more complicated. It has seven discrete proteins that come together simultaneously, forming complexes with triangular symmetry that include the adaptor function (i.e., allowing the complex to attach to the vesicle membrane).

The EMBL researchers pushed the envelope of cryoelectron microscopy to determine the nature of the “triads” called coatomers that make up the coat. They found that the seven proteins form two complexes that overlap into a layer 14 nanometers (nm) thick — a substantial fraction of the typical 100-nm-diameter vesicle. A Perspective article in the same issue of Science says there’s still a lot to learn about these coats: “it remains to be determined what specific roles these conformations play in the respective coat functions,” Noble and Stagg write. What is known is that the coatomer triads make contact with up to four neighboring triads. This gives them structural flexibility that is distinct from the other coated vesicle types. The authors of the paper speculate about the reasons for this:

In existing models for clathrin and COPII vesicle coats, multiple identical subunits each make the same set of interactions with the same number of neighbors. Structural flexibility allows formation of vesicles from different total numbers of subunits. Based on these principles, both clathrin-like and COPII-like models have been proposed for the assembled COPI coat. We found instead that assembled coatomer can adopt different conformations to interact with different numbers of neighbors. By regulating the relative frequencies of different triad patterns in the COPI coat during assembly — for example, by stabilizing particular coatomer conformations — the cell would have a mechanism to adapt vesicle size and shape to cargoes of different sizes.

The paper includes color models and two motion animations of how the proteins fit together, protecting the cargo as it rides to its destination from organelle to organelle.

Clathrin Coats

A better-understood protein coat is made of clathrin. The name comes from a Latin word for lattice. Individual clathrin molecules, made of 3 heavy chains and 3 light chains, look like a three-spoked pinwheel called a triskelion. They fit together beautifully around the vesicle into a cage-like structure that resembles a geodesic dome. A beautiful animation from Harvard Medical School shows how numerous other proteins work with clathrin to form the vesicle coat and disassemble it after use, so the triskelia can be recycled. The vesicles can import and export molecules to the exterior of the cell or transport them within the cytoplasm. Clathrin proteins are also implicated in cell division, where they assist in arranging chromosomes on the spindle.

The animation will need an update, because something new was reported about clathrin-coated vesicles (CCV) and the pits (CCP) that form when the membrane invaginates to bring cargo in from outside. Another EMBL team, also reporting in Science, found that clathrin is more gymnastic than previously recognized.

Unlike as shown in the animation, the clathrin lattice forms flat on the inner membrane surface before invagination begins. Then, as the membrane folds inward, the lattice stretches and reconfigures itself, maintaining the same surface area but following the shape of the vesicle as it elongates. With its cargo safely inside, the vesicle pinches off and forms a sphere. The press release from EMBL expresses the surprise at the shape changes:

John Briggs, senior scientist at EMBL Heidelberg, said: “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.”

(The “second model”, now falsified, refers to the idea that “clathrin assembles directly, assuming the shape of the membrane as it is drawn inwards.”) The paper describes how the growing cage must change its geodesic structure as the vesicle forms:

In order to bend, flat lattices composed primarily of hexagons must acquire pentagons requiring extensive molecular rearrangements and removal of triskelia.

Why would the cell perform this more difficult gymnastic routine? The final paragraph offers some possible reasons:

Recruitment of clathrin before membrane bending provides a flat, dynamic array as a platform for cargo recruitment. This implies that the membrane to be internalized and the size of the future vesicle are not determined by clathrin geometry during assembly into a curved cage but rather are selected before invagination during cargo recruitment. Rapid clathrin exchange is consistent with a dynamically unstable lattice — dynamic instability is a common property within networks of low-affinity protein interactions. It would allow for stochastic abortion of sites that initiate but fail to cross a growth- or cargo-mediated checkpoint before investing energy in membrane bending. During invagination, further exchange would allow clathrin reorganization and bending of the lattice into a defined cage that requires active disassembly.

One thing not mentioned in the articles is the rapidity of vesicle formation and disassembly. Suffice it to say that clathrin-coated endocytosis and exocytosis occur at the tips of nerve cells, where electrical signals must cross synapses. The vesicles form at one nerve, cross the synapse carrying the cargo, and are taken in by the next nerve cell in line. How long does it take your brain to feel pain from a stubbed toe? A lot of CCVs formed, crossed synapses, and disassembled in that very quick response!

Evolution or Design?

As usual, the articles and papers say very little about evolution. If mentioned at all, it was about the lack of evolution: e.g., “The archetypal protein coats COPI, COPII, and clathrin are conserved from yeast to human.” Only the Perspective piece by Noble and Stagg ventures further:

Individual proteins in the three different coat protein complexes share similar folds and are proposed to be distant evolutionary relatives. Despite these similarities, the coats have evolved different functional mechanisms….

One possibility is that the proto-COPI coat evolved the four different linkages to expand the repertoire of geometries that the coat can accommodate and thus adapt to the secretory needs of the cell.

These suggestions amount to little more than after-the-fact assertions of evolutionary belief. One cannot invoke a blind, unguided process to say that it “evolved to” meet the needs of the cell. Darwinian natural selection has no foresight.

The complexity of these coats, and the accessory proteins that build them, attach them to vesicles and disassemble them, defy unguided evolutionary explanations. They exhibit irreducible complexity; they don’t work unless all the protein parts are present simultaneously. They exhibit beauty in the way they organize into geometric shapes. The shapes, in turn, are dictated by digital codes in the genome that produce sequences that fold into building blocks. These building blocks, like the triskelion of clathrin, have no knowledge of the elegant geodesic domes that they will be fitted into. The triskelia are also blind to their attachment points that will be used by two other proteins that will disassemble the vesicle.

We see only glimpses of structures we don’t yet fully understand. Why are separate coats needed for the three types of transport? What types of vesicles need the different coats? What specific advantages do the different coats provide for transport in one direction and not the other? What molecules need coated vesicles opposed to uncoated vesicles? What function does each protein in the coat provide?

Further research at higher resolution will undoubtedly yield more knowledge about vesicular transport. One thing is clear so far; the elegance of these systems, their ability to reshape their geometry as they grow, their adaptability to cargoes of many sizes, the rapidity of their action, and their conservation from yeast to humans all proclaim, “design!”

Image: Left: A “triad,” building block of the COPI coat. Right: COPI coated vesicle made of an assembly of triads; by Svetlana Dodonova via EMBL.