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Scientists Reveal Bacterial T4SS “Biogenesis Machinery”

David Coppedge
Photo source: CDC, via Unsplash.

Bacteria have at least seven types of secretion systems that can inject material outside the cell. Many in the ID community have heard about the Type III Secretion System (T3SS) that some evolutionists unsuccessfully portrayed as a stepping stone to the bacterial flagellum. That turned out to be false, because it now appears that the T3SS is a descendant of the flagellum at best, and most likely an independent structure entirely. 

A number of years ago I wrote here about the Type IV Secretion System (T4SS). I reported how scientists including Gabriel Waksman from Birkbeck College and University College London were surprised to see how different it was from the T3SS. The T4SS is a large molecular machine (3 megadaltons) with 12 protein types, 92 proteins in all, arranged with multiple functional domains. Unlike some secretion systems that inject toxins into other cells, the T4SS is used by bacteria primarily for conjugation — the sharing of genetic information. The T4SS manufactures a pilus (thin, hairlike filament) through which proteins and genes can pass from one bacterium to another. 

The Return of Waksman

Now in new work by Mace et al., Waksman returns with colleagues to share their latest images of the T4SS at near-atomic resolution, using cryo-electron microscopy (see my report on “The Resolution Revolution”). The photos in Nature’s open-access paper, “Cryo-EM structure of a type IV secretion system,” are stunning. They sure look designed.

Bacterial conjugation is the fundamental process of unidirectional transfer of DNAs, often plasmid DNAs, from a donor cell to a recipient cell. It is the primary means by which antibiotic resistance genes spread among bacterial populations. In Gram-negative bacteria, conjugation is mediated by a large transport apparatus — the conjugative type IV secretion system (T4SS) — produced by the donor cell and embedded in both its outer and inner membranes. The T4SS also elaborates a long extracellular filament — the conjugative pilus — that is essential for DNA transfer. [Emphasis added.]

The T4SS, they say, “functions as a pilus biogenesis machinery,” building the conjugation tube from the base. Elements of the machine are named VirBx, numbered from 1 upwards. The central stalk in cross section has a pentameric symmetry; elements of VirB5 and VirB6 look like little stars stacked on top of each other into a stalk with a hole down the center. The pilus is constructed of VirB2 units that assemble in the inner membrane at binding sites. Then, they are “levered up” through the shaft to grow the pilus at the tip, spending ATP for energy in the process. The mechanism is somewhat reminiscent of cilium and flagellum assembly from the base to the tip, but these functional units are unique to pili.

How the Machine Works

The near-atomic images of the components allowed the authors to suggest a model of how the machine operates:

The data presented here suggest a model for pilus biogenesis by T4SS whereby five VirB2 subunits bound to five VirB6 subunits (Fig. 4f) are levered up to the assembly site, while five more are recruited to the vacated binding sites…. The previously described VirB2 dislocation function of VirB433 could comprise levering up VirB2 subunits from the recruitment site to the assembly site. The identities of the regions of VirB4 that act as a lever remain unclear. However, potential triggers may include binding of VirB1135 as well as ATP binding and/or hydrolysisAs layers of pentameric VirB2 are added, the pilus grows from the bottom, pushing the VirB5 pentamer out, passing through the arches, the I-layer (no conformational changes are needed (Extended Data Fig. 10k,l)), and finally through the O-layer channel, which is known to be flexible enough to open up(Extended Data Fig. 10k,l).

Thus, the near-atomic structure of a conjugative T4SSs presented here provides the structural basis for a plausible model for conjugative pilus biogenesis by T4SSs.

Only a Beginning

This sneak peak of how machines “capable of orchestrating pilus biogenesis” operate is only a beginning, since the authors note that the functions of several parts remain unclear. It’s clear enough, though, to arouse our wonder and awe. Could early microscopists watching pili form from one bacterium to another have ever imagined what really goes on? Literal molecular machines with moving parts like levers energized by ATP, using just-in-time assembly and quality control, are involved. That’s amazing.

The authors make a big deal about how all the parts for the machine are assembled into a working device:

This structure describes the exceptionally large protein–protein interaction network required to assemble the many components that constitute a T4SS and provides insights on the unique mechanism by which they elaborate pili.

It’s exciting to see molecular machines come into sharper focus. And the closer we look, the more elegantly engineered they appear. The authors have little to say about Darwinian evolution. They do speak of “co-evolution” of functional parts of the T4SS, but they are not referring to natural selection. Rather, they refer to how the components interact and fit together. One brief speculation about “evolutionary pressure” hardly adds to the research.

Today, bacteria evade our antibiotics by sharing resistance genes through conjugation, using their T4SS devices. The authors of the paper hope, therefore, that understanding the structural details of pili and the T4SS will help biochemists think of ways to thwart that sharing. But long before humans discovered antibiotics, bacteria were happily sharing genetic information and performing numerous beneficial roles for the biosphere (see herehere, and here). Scientists are also rapidly coming to the belief that “Horizontal Gene Transfer Happens More Often Than Anyone Thought,” as The Scientist reports.

A Machine Route from Free-Living to Parasite with T4SS

Are bad things we see the T4SS doing possibly the result of devolution? Phys.org reports on research by a team at Waginengin University in the Netherlands that might shed light on the origin of pathogenic bacteria. They speculate that pathogens emerged from free-living species when they took on a parasitic role in other microbes. If true, that would not be a case of progressive evolution, but rather of degeneration, like freeloaders taking the easy route of living off others.

The scientists examined numerous genomes of marine bacteria and found that pathogens in the Rickettsia family share many genes with marine microbes that are free-living in the ocean. Here’s where the T4SS makes a surprise appearance:

By comparing the genomes of the newly discovered species with those of previously known Rickettsiales, the team of researchers managed to reconstruct the evolution of host association and pathogenicity in the Rickettsiales. “We suggest that the free-living ancestor of Rickettsiales repurposed its needle-like type 4 secretion system to interact with and manipulate host cells,” Ettema speculates.

“Subsequently, many metabolic genes and genes affiliated with free-living lifestyle were lost as the ancestral Rickettsiales became more dependent on its host for metabolites and energy. This was then mirrored by the acquisition of genes involved in host manipulation and energy parasitism,” he adds.

Maybe some of mankind’s worst plagues “devolved” from “responsible” microbes that were free-living and doing good for the community. After all, devolution is much easier (and therefore much more likely) than progressive evolution. If a microbe already had a T4SS, it would have been a relatively simple degenerative route for it to support a freeloading lifestyle. The pathogen didn’t invent new information. It tossed genes overboard in the process of surviving, like Michael Behe suggested in one of his analogies for his book Darwin Devolves. Indeed, the research team identified a fair number of genes that the pathogens had apparently lost.

Research along these lines might start a trend away from Richard Dawkins’s world of selfish genes, where everything is only concerned about its own survival. If Michael Denton’s picture of prior fitness for complex life is followed, as he describes it most recently in The Miracle of Man, then researchers can see how some good mechanisms might have been short-circuited. Whether by entropy or accident, a few typos don’t always render a message unreadable. The message of design remains loud and clear.